PL93115B1 - - Google Patents

Description

The subject of the invention is a method for preparing new pyrimidines of the general formula I, wherein R1 is an alkoxy group having 1-3 carbon atoms, a morpholino, thiomorpholino, 1-oxidothiomorpholino or 1,1-dioxydothiomorpholino group or a piperazine group, which in position 4 may contain an alkanoyl group having 2-4 carbon atoms, an optionally substituted methoxy, carboxyl or acetyl group, or an aminocarboxonyl group, optionally substituted by one or two alkyl radicals having 1-4 carbon atoms or a methoxymethyl radical, or in this position contains a pyridinoyl, salicyloyl or furanoyl group or an alkylsulfonyl group having 1-3 carbon atoms, R2 is a group morpholino, thiomorpholino, 1-oxidothiomorpholino or 1,1-dioxidothiomorpholino, or a piperazino group, an optionally substituted alkanoyl group with 2-4 carbon atoms in the 4-position, an optionally substituted acetyl group, R3 is a hydrogen, chlorine or bromine atom, a nitro group va, cyano, formyl or acetyl, and R4 is a hydrogen, chlorine or bromine atom, a cyano group or an amino group, substituted with a cyclohexyl radical, a pyridyl radical or a phenyl radical which is optionally substituted with a chlorine atom, a carboxyl group or a carbomethoxy group, or R4 is a group carphoalkoxy with 2-4 carbon atoms, radical alkyl group with 1-6 carbon atoms, optionally substituted with 1 or 2 carboalkoxy groups with 2-4 carbon atoms, a hydroxyl or mercapto group, optionally substituted with an allyl radical or an alkyl radical with 1-6 carbon atoms, or an 1-oxidothiomorphol group, as well as physiologically acceptable addition salts of these compounds with inorganic or organic acids. The compounds prepared by the method according to the invention have valuable pharmacological properties, in particular they counteract thrombosis, partially without affecting blood pressure, and especially those compounds which are acylated at the nitrogen atom of the piperazine ring do not affect blood pressure. Compounds of formula 1, in which all symbols have The leaving group is prepared according to the invention by reacting a compound of the general formula II, wherein R5 has the meaning given above, one or two substituents X and Y and/or Z represent a convertible group such as a halogen atom, a hydroxyl group, a mercapto group or a sulfonic acid residue, a substituted alkyl, aralkyl or aryl hydroxyl, mercapto, sulfinyl or sulfonyl group, and the remaining substituents X, Y and/or Z have the meaning given above for R1, R2 and R4, with a compound of the general formula III, wherein A has the meaning given above for R19, Rg and/or R4. The above-mentioned leaving group is especially a halogen atom, such as a chlorine or bromine atom, a hydroxyl group, a mercapto group or a sulfonic acid group, a hydroxyl, sulfinyl or sulfonyl group substituted with an alkyl, aralkyl or aryl radical, such as a methoxy, ethoxy, phenoxy, methylthio, benzylthio, methylsulfinyl, methylsulfonyl or ethylsulfonyl group. Depending on the reactivity of the group to be replaced or the group to be left off, the reactions are carried out at a temperature of -20°C to 250°C, optionally in the presence of an acid-binding agent and preferably in a solvent such as dioxane, acetone, glycol dimethyl ether, dimethylformamide, dimethyl sulfoxide or ethanol, or in an excess of the amine of the general formula III used. However, these reactions can also be carried out without solvent.In the preparation of compounds of general formula 1, in which < R2 and/or R4 represent a piperazine group free in position 4, it is advantageous during the reaction to protect the imine group in the compound of general formula II and/or the imine group in the appropriately substituted amine of general formula III in a known manner, e.g. by means of an acyl group such as a carboethoxy, formyl, acetyl or benzoyl group. This protecting group can then be cleaved again, for example hydrolytically in the presence of an acid or a base, at the boiling point of the solvent used or lower. The cleavage of the acyl group in S-oxide compounds is, however, preferably carried out by hydrolysis in the presence of a base, e.g. potassium hydroxide. If a compound of the general formula I containing a thiomorpholine group is obtained by the process according to the invention, this compound can be converted by oxidation into the corresponding S-oxide or S,S-dioxide, and if the obtained compound of the general formula I contains a piperazine group whose imino group is substituted by an acyl or aminocarbonyl group, it can be converted by hydrolysis into the corresponding piperazine compound of the general formula I not substituted in the 4-position. If the obtained compound of the general formula I contains a free imino group, it can be converted by acylation or carbamoylation into the corresponding a compound of the general formula I, and if the resulting compound of the general formula I contains a hydrogen atom in position 5, this compound can be converted by nitration into the corresponding nitro compound of the formula I. The oxidation process, if necessary, is preferably carried out using customary oxidizing agents, such as hydrogen peroxide, peracetic acid, sodium periodate or potassium permanganate, preferably in a solvent, e.g. acetic acid, in particular at a temperature of 0° to 80°C. If oxidation is carried out, for example, with hydrogen peroxide, peracetic acid or sodium periodate, the S-oxide compound of the general formula I is preferably obtained, but if oxidation is carried out with potassium permanganate, the S,S-dioxide compound of the general formula I is preferably obtained. The hydrolysis, if necessary, is carried out in the presence of a base, such as sodium or potassium hydroxide, or an acid, such as hydrochloric acid, preferably in a solvent, such as water, ethanol, isopropanol or ethanol/water, and preferably at the boiling point of the solvent used, e.g. at 80°C to 100°C. The acylation, if used, is preferably carried out with the corresponding carboxylic acid in the presence of a water-removing agent, such as e.g. N,N-dicyclohexylcarbodiimide or thionyl chloride, or with a reactive derivative of a carboxylic acid, for example with a halide, anhydride, ester or mixed anhydride, optionally in the presence of a base such as sodium carbonate, triethylamine or pyridine, preferably in a solvent such as ether, dioxane, benzene or pyridine and at a temperature of 0°-100°C. Optional nitration of the obtained compound is carried out with a nitrating agent such as nitric acid with sulfuric acid or nitric acid alone at an elevated temperature, e.g. 50-80°C. The compounds of formula II used as starting products are partly known from the literature or can be prepared by known methods /see clades/. In this case, it is possible to prepare a compound of general formula I containing only one or two replaceable groups in the pyrimidine ring by reaction with a compound of formula 3. On the other hand, it is also possible to additionally convert in the compound of general formula 2 such groups X, Y and/or Z which are not replaceable groups, e.g. the thiomorpholinopyrimidine group can be additionally oxidized, the formylpiperazine group can be additionally deacylated or the thio group can be alkylated. Also, the exchange of a replaceable group for a group with an even higher reactivity enables the preparation of starting compounds of formula 2. The obtained compounds of general formula 1 can, if necessary, be converted into salts with Physiologically acceptable acids, e.g. hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid. As mentioned in the introduction, the compounds prepared by the method according to the invention have valuable pharmacological properties, and in particular they very strongly inhibit the formation of platelet aggregations and their ability to adhere. The ability to prevent platelet aggregation can be demonstrated, for example, by the method of Born and Cross [J. Pnysiol. 170, 397 /1964/] or the method of K. Breddin {Schweiz. Med. Wschr. 95, 655—600 /1965/], and the effect on the ability to adhere is determined by the so-called injection test. washing, e.g. Morris method /E. Deutsch, E. Gerlach and K. Moser: 1. Interndbionales Symposiura liber Stoffwedhsel und Mernbranpermeabilitat von 40 45 50 55 605 93 115 6 Erythrozyten und Thrombozyten, Wieden 1969, ed. Georg Thieme, Stuttgart/. The Born and Morris method tested, for example, the following compounds: A=6-methyl^5-nitro-2'-piperazine-4-/l-oxy dothiomorpholino/-pyrimidine, B= 6Hiethyl-5-nitro-2^piperazine-4-thiomorpholino-pyrimidine, C=acid nitrile 5-cMoro-2-piperazine-4-/l-oxido- thiomorpholino/-6-pyrimidinecarboxylic acid, D=6-etcksy-5-nitro-4-/l-oxidothiomorpholino/-2-piperazinopyrimidine, E=5-nitro-4-/l-oxydothiomorpholino/-2-piperazine-6-iscpropoxypdrimidine, * F=6-II-s.ibutoxy-4-/l ,1-dioxydothiomorpholino/-5-nitro-2-»piper.azinopyrimidine, G=6-methylthio-5-niltro-4-/l-o:oxydothiomorpholino/-2-formylpiperazinepyrimidine and H=6-methyl-5-ndtro-4-/l-oxidothiomorpholino/-2- -acetoacetylpiperazinopyrimidine. 1. Marking focus platelets using the Morris method. To determine the ability of the tested substances to prevent platelet aggregation, 1 ml of human blood is pipetted into small test tubes and the test substance is added in such an amount that its final concentration is 10-5 mol/liter or 1 10-5 mol/liter. The test tubes are cultured at 37°C for 10 minutes, after which 1 g of glass beads (glass beads for gas chromatography, BDH Poole, Great Britain) is added to half of the test tubes. Then the closed test tubes are mounted on a rotating disc around a horizontal axis and the disc is rotated for 1 minute, bringing the glass beads into good contact with the blood. Then (the blood is left in the same test tubes for another hour at room temperature, A satisfactory sedimentation of red blood cells takes place. Samples of 0.01 ml are taken from the plasma constituting the upper layer, diluted with a solution for coelomoscopy in a ratio of 1:8000, and the platelets are counted using a coelomscope, determining the percentage reduction in adhesion under the influence of the tested substance, compared with the results obtained for test tubes without glass beads. Average results from 4-6 tests are given in the table. 2. Determination of platelet aggregation (blood) by the Born and Gross method. The degree of platelet aggregation is measured in the blood plasma of healthy persons containing a significant number of these platelets, and the course of the decrease in optical density after the addition of adenosine diphosphate is measured photometrically and recorded. The velocity of platelet aggregation is determined from the angle of the density curve, whereby This point on the curve, which corresponds to the greatest light transmittance, is used to calculate the "optical density". The doses of adenosine diphosphate used are as small as possible, but such that they cause irreversible focusing. Before adding adenosine diphosphate, plasma samples are cultured at 37°C for 10 minutes with the addition of various amounts of the test substances. 3. The acute toxicity of the test compounds is determined in mice by carrying out observations over a period of 14 days, partly as orientation tests, or the LD50 is determined on the basis of the percentage of animals that die during the observations after receiving various doses {see J. Pharmacol. exper. 96, 99 /1949/]. The results are also given in the table. Table Test substance A B C D £ F G 1 H Morris test % inhibition at 10 millimoles/liter 92 66 92 100 69 61 2 11+ Born test with adenosine diphosphate EC50 1.2X10-8 3X10~« 1.3X10-7 2.5X10-8 2X10-7 ,8.5X10-7 5X10-6 io-4 LD50 mg/kg intravenous 160 70 101 150 170 150 oral 600 620 836 600 500 1500 1000 1000 */ Concentration of 30 millimoles/liter. In the Born test, the EC50 also means the concentration in moles/liter at which a 50% change in "optical density" is obtained. For pharmacological purposes, the compounds of general formula I or their salts can be used together with other active substances in the form of preparations such as dragees, tablets, suppositories or solutions, these preparations being prepared by known methods. A single dose of these compounds for adults is 10-500 mg, preferably 20-150 mg. The invention is illustrated in the following examples, where the examples marked with letters describe methods for preparing the starting products, while the examples marked with Roman numerals describe the process according to the invention. Example A. 2-,carboethoxypiperazine-4-chloro-6-amino-pyrimidine. 29.0 µg 2,4-Dichloro-6-aminopyrimidine £H. Bretsehneider et al. Monatsh. f. Ohemie 92, 132 /1961/] is mixed with 150 ml of dioxane, the obtained suspension is heated to 80°C and treated with 60.2 g of N-carboethoxypiperazine, and then left for 40 minutes at this temperature. Then the mixture is poured into 500 ml of water and cooled in an ice bath while stirring. The product, which initially has an oily consistency, crystallizes after about 150 minutes. It is filtered off and crystallized from 300 ml of methanol, obtaining 28.8 g of 2-carboethoxy-4-chlor-6-aniinopyrimidine at 163-166°C, which is 57.3% of theory. Example B. 2-Carboethoxypiperazine-4,6-dichloropyrimidine. 79.0 g of 2-methylthiobarbituric acid [Koppel, Springer and Robins, J. Org. Chem. 26, 792-803 (1961)] and 94 g of carboethoxypiperazine in 1100 ml of dimethylformamide are heated at 120°C for 3 hours, during which 40 45 50 55 6093115 7 8 methyl mercaptan is volatilized. Then the mixture is cooled, diluted with water and stirred until crystals of 2-carboethoxypiperazine are obtained. 2-chlorocarbonylpiperazine-4,6-dichloropyrimidine. 68.6 g of product was obtained, which constitutes 51.4% of theoretical yield. 13.4 g of the crude product obtained was boiled with 92 ml of phosphorus oxychloride for 1.5 hours and then evaporated to dryness. The residue was stirred with ice, the precipitate was filtered off, and boiled under reflux with ethanol for 4 hours to completely convert the 2-chlorocarbonylpiperazine-4,6-dichloropyrimidine formed simultaneously into 2-carphoethoxypiperazine-4,6-dichloropyrimidine, the reaction being monitored by thin-layer chromatography on a gel plate. silica gel, eluting with n-pentane/ethyl acetate 7:3. After evaporation of the alcoholic solution, the product was obtained in the form of white crystals. 37.9 g of product were obtained, melting at 136-143°C, which is 49.9% of the theoretical yield. Example C. 4-Thiomorphodino-2,6-rimidine. 271 g of 2,4,6-trichloropyrimidine were dissolved in 1.8 liters of acetone and slowly poured, with stirring, into a mixture of 250.3 g of triethylamine and 170.5 g of thiomonofoline in 0.7 liter of acetone so that the temperature of the mixture did not rise above 40°C. Then stirring was continued for a further for 46 minutes, during which the temperature dropped again to 30°C. The precipitated triethylamine hydrochloride was filtered off, washed with acetone, and the filtrate was evaporated on a rotary evaporator. The residue was recrystallized from 2.3 liters of ethanol, obtaining 222.7 g of 2,6-dichloro-4-thiomorpholinopyrimidine as white crystals. The product was recrystallized again from 2.2 liters of ethanol, obtaining 196.15 g of pure white crystals as the first fraction. After concentrating the mother liquor, an additional 17.9 g of product was obtained, giving a total of 214.4 g of product, which constitutes 57.1% of the theoretical yield. The product melted at 118-121.5°C. Example D. 2-Thiomorpholino-4,6-dichloropyrimidine. From the mother liquor obtained after the first crystallization in the process described in Example C, the simultaneously formed 2-thiomorpholino-4,6-dichloropyrimidine is obtained quantitatively. For this purpose, the mother liquor is evaporated and the residue is chromatographed on a silica gel column with grains of 0.2-0.5 mm/W, eluting with toluene, at a ratio of substance to silica gel of 1:10. The first fractions contain the entire amount of the product. The yield of 79.0 g is 21.0 t of theory. The product melts at 79.5-81.5°C. Example B. 2-Formylpipephasyl-4-Vl-oxidothiomorpholino-5-nitro-6-chloropyrimidine. 100 g of 2-formylpipephasyl-4-thiomorpholino-6-chloropyrimidine, melting at 195°C, is added portionwise with stirring to 570 ml of concentrated sulfuric acid, while cooling occasionally to maintain the temperature of the mixture at about 20°C. Then it is stirred until the starting substance is completely dissolved, which takes about 30-10 minutes, after which it is cooled to 0°C, and 115 ml of fuming nitric acid is slowly added dropwise to the solution, maintaining the temperature at about 5°C by good ice cooling. After the addition is complete, stirring is continued for an additional The resulting cold yellow solution was stirred for 20 minutes and the resulting cold yellow solution was stirred with about 3 liters of crushed ice, whereupon a greasy yellow product precipitated. The product was extracted with 1.2 liters of chloroform and then with two 0.7 liter portions of chloroform, the combined extracts were dried over sodium sulfate and evaporated in a rotary evaporator. The resinous yellow residue was dissolved in 1.1 liters of hot ethanol, cooled slowly to -30°C, and seeded with crystals. Stirring was continued for 1 hour at room temperature, then cooled with ice water until crystallization was complete. After 20 minutes, the product was filtered off at about 5°C, and the precipitate The mixture was washed with cold ethanol and dried in a desiccator over sulfuric acid. 104 g of product were obtained, melting at 176-178°C, which is 87.74% of the theoretical yield. In an analogous manner, 6-ethoxy-5-nitro-4-(1-oxidothiomorpholino)-2-piperazinopyrimidine was obtained from 6-ethoxy-2-piperazine-4-thiomorpholinopyrimidine and concentrated sulfuric acid with concentrated nitric acid. Before extraction with chloroform, the pH of the mixture was adjusted to 9 with sodium hydroxide. The product, recrystallized from ethanol, melted at 223-224°C. Example F. 2-Methylmercapto-4-thiomorpholinopyrimidine no-5-nitro-6-cyclohexylaminopyrimidine. 14.0 g 2-methylmer'capto-4,6-dichloro-5-nitropyrimidine /Brown and Jacobsen, Soc. 1963, 3776/ is dissolved in 200 ml of methanol, cooled to -60°C and treated with 6.0 g of triethylamine, and then, within 1 hour, 4.0 g of cyclohexylamine is added dropwise with stirring so that the temperature of the mixture is not higher than -60°C. Then the methanol is distilled off, the residue is dissolved in chloroform and washed five times with water, then the chloroform is distilled off and the residue is recrystallized from isopropanol, obtaining 11.2 g 2-methylmercapto-4-chloro-5-nitro-6-cyclohexylaminopyrimidine, 62% of theoretical yield. The product melts at 98-104°C. 3.0 g of the product obtained was dissolved in 1 ml of acetone, a solution of 1.38 g of potassium carbonate in 1.5 ml of water was added, and a solution of 1.2 g of thiomorpholine in 10 ml of acetone was added. The mixture was then stirred thoroughly at room temperature, and after a short time a large crystalline precipitate precipitated, the volume of which increased with the addition of water. This product is filtered off and recrystallized from isopropanol to obtain 2.3 g (G2°/e of theoretical yield) of 2-methylmercapto-4-thiomo(rphoHno-5-nitro-6-cyclohexylaminopyrimidine, melting point 145-146°C. Example G. 2-(1-oxidothiomorpholine)-4-formylpiperazine-5-nitro-6-chloropyrimidine. This compound is prepared in a manner analogous to that described in Example sulfuric acid. The product melts at temperature 110-^L3&0C9 and the yield of the process is 89.4% of theory. Example H. 2-Thiomorpholino-4-chloropyrimidine and 4-thiomorphino-2-chloropyrimidine. To a solution of 8.0 g (0.054 mol) of 2,4-dichloropyrimidine in 1330 ml of acetone was added dropwise, with stirring at -35°C, a solution of 6.1 g (0.059 mol) of thiomorpholine in 15 ml of water and a solution of 8.1 g (0.059 mol) of potassium carbonate in 15 ml of water. The mixture was stirred for 2.5 hours at room temperature, the acetone was evaporated under reduced pressure, the residue was washed with water, dried and Chromatography on 250 g of silica gel of activity I and grain size 0.05-0.2 mm, eluting with benzene and ethyl acetate 5:1. A substance with a high RF value is 2-thiomorpholinopyrimidine, which, after recrystallization from isopropanol, melts at 64-65°C. 0.7 g of product is obtained, which is 6% of theory. A substance with a low RF value is 4-thiomorpholino-2-chloropyrimidine, which, after recrystallization from isopropanol, melts at 106-108°C. 8.9 g of this compound are obtained, which is 77% of theory. The following compounds are prepared in a similar manner: 5-cyano-2,6-dichloro-4-thiomorpholine, melting point 180°C, in a yield of 41.7% of theory, -cyano-4,6-dichloro-2-thiomorpholinopyrimidine, melting point 99°C, in a yield of 4.5% of theory, where 5-cyano-2,4,6-trichloropyrimidine and thiomorpholine are used as starting products, and b) 5-cyano-2,4-dichloro-4-methoxypyrimidine, melting point 137°C, in a yield of 29.4% of theory, and 5-cyano-4,6-dichloro-2-methoxypyrimidine, melting point 156°C, with a yield of 10% of the theoretical yield, if 5-cyano^2,4,6^trioMoropyrim, idine and methanol are used as starting products, and the reaction is carried out for 20 hours at a temperature of 65°C, without the addition of potassium carbonate. Example I. 6-ethoxy-4-chloro-2-methylthio-5-nitropyrimidine. 24 g (0.1 mol) 4,6-dichloro-2-methylthio-5-nitropyrimidine (preparation method see Brown, Jacobsen, J. Chem. Soc. 1965, 3776/ is mixed with 200 ml of ethanol at 0°C and added dropwise to the obtained suspension with stirring at 0°C in A sodium ethanolate solution prepared from 2.35 g (0.102 g-atom) of sodium and 80 ml of ethanol was stirred for 20 minutes, and then stirred for a further 45 minutes at 0° C. The reaction mixture was then poured into 700 g of crushed ice, the separated yellow crystals were filtered off, dried and recrystallized from petrol (boiling point 60-100° C). 20.8 g (3.5% of theory) of 6-ethoxy-4-chloro-2-methylthio-5-nitro-pyrimidine was obtained, melting at 83-65.6° C. In a similar manner, by reacting 4,6-dichloro-2-methylthio-5-nitro-pyrimidine with the appropriate sodium alkoxide, the following compounds are produced: a/ 4-chloro-6-methoxy-2-methylthio-5-niitropyrimidine, which after recrystallization from gasoline melts at a temperature of 77.5-79.5°C, b/ 4-chloro-2-methylthio-5-nitro^6-n-propoxypyrimidine with an oily consistency, RF=0.4, purified on silica gel by eluting with benzene from gasoline 1:1, c/ 4-chloro-6-isoptopoxy-2^methylothio-5-nitropyrimidine, which, recrystallized from gasoline, melts at 55-57°C, d/ 6-allyloxy-4-chloro-2-methyltóo-6-nitropyrimidine o 6-methylbutoxy-4-chloro-(2-methylthio-5-nitropyrimidine) of an oily consistency, RF = 0.45 after purification on silica gel by elution with benzene/petrol 1:1, i.e. 6-sec-butoxy-4-methylthio-5-nitropyrimidine of an oily consistency, RF = 0.45 after chromatography on silica gel using benzene/ethyl acetate 1:1, and g) 4-chloro-2-methylthio-neopentyloxy-5-nitropyrimidine of a boiling point 98-103°C/0.01 mm Hg. Example J. 6-ethoxy-2-methylbthio-4-(1-oxy-dothiomorpholino)-5-nitropyrimidine. g (0.06 mol) of 6-ethoxy-4-cMoro-2-methyli100-5-nitropyrimidine and 5 g of potassium carbons are mixed with 150 ml of ethanol and a solution of 7.8 g (0.066 mol) of 1-oxidothiomorpholine in 100 ml of ethanol is added to the obtained suspension, and the mixture is heated. weighed under a reflux condenser at 0°C for 4 hours. Then the mixture is poured into ice water, the yellow crystals are filtered off, dried and recrystallized from ethyl acetate, adding activated carbon. 17.7 g (88.5% of theoretical yield) of 6-ethoxy-2-methylthio-4-(1-oxidothiomorpholino)-5-nitropyrimidine are obtained at a temperature of 160-162°C. The following compounds are prepared in a similar manner: a) from 6-ethoxy-4-chloro-2-methylthio-5-niltropyrimidine and thiomorpholine, 6-ethoxy-2-methylthio-4-thiomothypholino^5-nitropyrimidine is obtained, which, recrystallized from ethyl acetate/benzine, melts at a temperature of 117.5-0195°C, b/ from 6-ethoxy-4-chloro-2-methylthio-5-nitropyrimidine and 1.1-dioxydothiomorpholine, 6-ethoxy-methylthio-5-niitro-4(1,1-dioxydothiomorpholino)-pyrimidine with a melting point of 100-163°C (from ethyl acetate), 6-ethoxy-2-methyl-thio-4^orpholine-5-nitropyrimidine with a melting point of 114.5^1160C (from ethanol), 60 d/ from 4-chloro-6-methoxy-2-methylthio-,5-nitropyrimidine and 1-oxidothiomorpholine, by reaction at 20°C for 15 hours, are obtained 6-Methoxy-[beta]-methylthio-5-nitro-4-(1-oxido-morpholino)-pyrimidine, m.p. 175-177.5°C (from ethanol), (e) from 6-allyloxy-4-chloro-2-methyl-1-5-nitropyrimidine and thiomorpholine, by reaction at 20°C for 2 hours, gives 6-allyloxy-2-methylthio-5-nitro-4-thiomorpholinopyrimidine, m.p. 89-90°C (from petrol, b.p. 60-80°C), (f) from 6-allyloxy-4-chloro-2-methylthio-5-nitropyrimidine and thiomorpholine, m.p. 89-90°C (from petrol, b.p. 60-80°C), midine and 1,1-dioxydothiomorpholine, by reaction at 20°C for 2 hours, 6-aloxy-4-(1,1-dioxydothiomorpholino)-2-methylthio-5-nitrpyrimidine with a melting point of 147-149°C is obtained (from gasoline with a boiling point 60-10°C mixed with ethyl acetate in a ratio of 2:3/, %1 of 4-chloro-2-methylthio-5-nitro-6-n-propoxypyrimidine and 1,1-dioxydothiomorpholine gives 4-/l,1-dWiUoxydothiomorpholine/-2-methylthio-5-ni- tro-tf^n-propoxipyrimdine with melting point 160-'l"fl2°C (from isopropanol), h/ from 4-chloro-2-methylthio-i5-ni'tro-6-n-propoxypyrimidine and 1-oxydothiomorpholine 2-methyl1;io-5-ni:tro-4-(l-oxidothiomorpholino/^6-n-propoxypyrittifdine with a melting point and/ from 4-chloro-2-methylthio-5-nitro-6-n-propoxypyrimidine and morpholine, 2-methylthio-4-morpholino-5-nitro-i6-n-pixpoxypyrimidine with a boiling point of 89-90°C (from isopropanol), k/ from 4-chloro-2-methylthio-5-nitro-6-isopropoxypyrimidine and 1,1-dioxydothiomorpholine, 4-(l.l.diolcysydothiomorpholmo)-2-methyl,thio-5-nitro-6-isopropoxypyrimidine with a melting point of 168-170°C (from isopropanol), , 1/ with 4-cMoro-2-methylthio-5-nitro-6-isopropoxypi- rimidine and 1-oxidothiomorpholine, 2-methylthio-5-nitro-4-(1-oxidothiomorpholine) -6-isopropoxypyrimidine with a melting point of 127-129°C (from isopropanol), 2-methyl-thio-5-ni'tro-6-isopropoxy-4-thiomorpholmopyrimidine, melting point 97-98.5°C (from -benzine), n/ from 4-chloro-2-methylthio-5-nitro^6-isopropoxypyrimidine and morpholine 2-methylthio-4- -morpholino-5-nitro-6-isopropoxypyrimidine o melting point 80-81 °C (from gasoline), 6-n-butoxy-4-chloro-2-methylthio-5-nitropyrimidine and 1,1-dioxydothiomorpholine give 6-n-butoxy-4-(1,1-dioxydothiomorpholine) with a melting point of 128-130°C (from ethanol), 6-n-butoxy-2-methylthio-5-nitro-4-(1-oxidothiomorpholino)-pyry is obtained from e-n-butoxy^-ohloro^-methylethio-S-nitropyrimidine and 1-oxydothiomorpholine -130.5°C ethanol/, q/ z 6-n-lbutoxy-4-chloro-2-methylthio-5-nitropyrimidine and thiomorpholine give 6-n-ibutoxy-2-methylthio-5-nitro-4-thiomorpholinopyrimlidine with melting point 107-109.5°C (from cyclohexane), r/ from 6-n-butoxy-4-chlorone-2-methylthio-5-nitropyrimidine and morpholines give 6-n-butoxy-2-methylthio-4-morpholino-5-iitropyrimidine with a melting point of 98-1000°C (from cyclohexane), s/ from 6-II-butoxy-4-chloro-2-methylthio-5-nitropyrimidine and 1,1-dioxydothiomorpholine 6-second-butoxy-4-(1,1-dioxydothiomorpholino)-2-methylthio-5-nitropyrimidine with a melting point of 1162.5-114.5°C (from ethanol) is obtained, tropyrimidines and 1-oxydothiomorpholines, 6-II-butoxy-2-methylthio-§-nitroi4-(1-oxydothiomorpholino)-pyrimidine with a melting point of 121.5-123°C (from ethanol) is obtained from 6-II-butoxy-4-chloro-2-methylthio-5-nitropyrimidine and thiomorpholines are obtained 6-II-butoxy^-methylethio^S-ritro^-thiomorpholtnopyrimidine with a melting point of 87.5^89.5°C. /from cyclohexane/, v/ from 4-chloro-2-methylthio-6-neopentoxy-5-nitro-pyrimidine and 1-oxy dothiomorpholine 2-methylthio-6-neopentoxy-5-n-rtro-4-(l-olxidothio-2B morpholino)-pyrimdine with a melting point of 125-127°C is obtained /from ether dinisopropyl/ and w/ from 4-chloro-2-matylphthio-6-neopentoxy-5-niltro-pyrimidine and thiomorpholine 2-methyl- thio-6-neopentoxy-5-nitro-4-thiomorpholinopyrimidine^ with a melting point of 102-104°C (from ethanol). Example K. e-chloro-E-methylthio-S-nitro -4- (1-oxidothiomorpholino) ipyrimidine. 36 g (0.15 mol) of 4,6-dichloro-2-methyl)thio-5-nitropyrimidine are dissolved in 100 ml of acetone and, after cooling to -50°C, 35.7 g (0.3 mol) of 1-oxydothiomorpholine are added dropwise to the solution with stirring, and then stirred for another hour and then pour it into ice, filter off the precipitate formed, dry it and recrystallize it from ethyl acetate, obtaining 6-chloro-2-methylthio-5^niltro-4-(1-oxydbthiomorpholino)-pyrimidine, melting point 160-102°C. The efficiency of the process is 80.4% of the theoretical yield. The following compounds are prepared in a similar way: a/ from 4,6-dichloro-2-methylylthio-5-nitropyrimidine and thiomorpholine, by reaction at -50°C for 80 minutes, 6-chloro- -2-methylthio-5-nitro-4-thiomorphollinopdrymidine, melting point 138-140°C (from a 2:3 mixture of gasoline and ethyl acetate) and b/ from 4,6-diUchloro-2-methyl[thio-5-nitropyrimidine and concentrated ammonia, 4-amino-6-chloro-2-methylthio-5-nd-tropyrimidine with a melting point of 176-177.5°C (from carbon tetrachloride) is obtained. Example L. 6-amino- 2-Methylthio-5-nitro-4-(1-oxidothiomorpholino)pyrimidine. 3.08 g (0.014 mole) of 4-chloro-4-amino-2-methylthio-5-nitropyrimidine was dissolved in 50 ml of acetone, and a solution of 3.2 g (0.027 mole) of 1-oxidothiomorpholino in 20 ml of acetone was added dropwise to the solution with stirring at room temperature. The mixture was stirred for 1.5 hours, and then ice was added to the mixture. The precipitate was filtered off and recrystallized from ethanol, yielding 6-amino-2-methyl-13-thio- <5-nitro-4-(1-oxidothiomorphOlino/-pyrim-idine) with a melting point of 239^242°C, with a yield of 7(8*2% of the theoretical yield. Example M. 2-(N-carboethoxyp4rperazine)-4,6-dihydroxyH5-nitroipyrinidine. 100 g (0.493 mol) of 2,4-dihydroxy-2-methylthio-5-ritrapyrimidine (prepared by the method of Brown, Jacobsen, J. Chem. Sec. 1965, 3776) together with 156 g (0.986 mol) of N-carboethoxypiperazine are heated with stirring at 120°C for 30 minutes, then it hardened into a solid mass the post-reaction mixture is recrystallized without further treatment from ethanol, obtaining 140.5 g (91.1°C) with a theoretical yield of 2(N-carboetooxypiperazine)-4,6-dihydroxy-5-nitropyrimidine with a melting point of 220-24°C. method, from 4,6-dihydroxy-2-methylthio-5-nitropyrimidine and thiomorpholine, 4^6-dihydroxy-5-nitro-2^thiomorpholinopyrimidine with a melting point of 220-223°C is obtained. Example 1100 ml of phosphorus oxychloride and 190 ml 19.0 g (0.735 mol) of 2,4-dihydroxy-5-nitro-2-thiomorpholinopyrimidine was added portionwise to diethylaniline, while the temperature of the mixture rose to 60°C. The mixture was then refluxed for 3 hours, then 600 ml of phosphorus oxychloride was distilled off and the residue was carefully poured onto ice. The aqueous phase was extracted with chloroform, the extract was dried over sodium sulfate, treated with activated charcoal and evaporated to dryness. The residue was recrystallized twice from benzene/petrol, yielding 44 g (2K), 4% of theory) of 4,6-dichloro-5-nitro-2,4-thiomorpholinopyrimidine. pyrimidine with a melting point of 164-105°C. In a similar manner, from 2-(N-carboethoxyipiperazine)-4;6-dihydroxy-5-nitropyrimidine and phosphorus oxychloride, 2-(N-perazine/^^-dichloro^-nitropyrimidine with a melting point 120-I121.5^C (from gasoline). Example O. '6-ethoxy-4-chloro-5-nitro-2-thiomorphoMnopyrimidine. 14.6 g /0.05.mol/ 4.6^dihaoro-5-nitro-2f-thiomorpholinopyrimidine is dissolved in a mixture of 200 ml of acetone and 200 ml of dioxane, the solution is cooled to -20°C and, with stirring at this temperature, a solution of sodium ethoxide prepared from 1.15 g (0.05 mole) of sodium and 100 ml of ethanol was added dropwise to the solution. The mixture was stirred at room temperature for 1 hour, then poured onto ice, the precipitate was filtered off and recrystallized from isopropanol, yielding 10.3 g (67.5% of theory) of 6-ethoxy-4-chloro-5-nitro-2-thiomorpholinopyrimidine, melting at 149-150°C. Example P. 2-(N-cariboethoxypiperazino)-6-chloro-thiomorpholinopyrimidine. 7.0 g (0.02 mole). 2-(N-Carboethoxypiperazino)-4,€-dichloro-5-nitropyrimidine was dissolved in 100 ml of acetone, then a solution of 5 g of potassium carbonate was added dropwise to the solution at -40°C, followed by a solution of 2.1 g (0.02 mole) of thiomorpholine in 30 ml of acetone, with stirring. The mixture was stirred at -40°C for 2 hours, then at room temperature for 1.5 hours, poured onto ice, the precipitate was filtered off, dried, and recrystallized from petrol/ethyl acetate, yielding 5.3 g (64.7%) of theoretical yield of 2-(N-Carboethoxypiperazino)-6-chloro-5-nitropyrimidine. -4-thiomorpholinopyrimidines, melting point 134.5^1&6.5°C. Example Q. 6-ethoxy-2npiperazine-4-thio,morpholinopyrimidine. 9 g (0.03 mol) of 6-chloro-2-(N-formylpiperazino)-4-thiomorpholinopyrimidine with a melting point of 196-201°C are added to a solution of sodium ethoxide prepared from 2.3 g (0.1 mol) of sodium and 150 ml of ethanol, and then the mixture is heated in an autoclave for 2 hours at 220°C. After cooling, the mixture is poured into water, extracted with chloroform, the extract is dried over sodium sulfate and evaporated to dryness. The remaining material is purified by chromatography on silica gel 0.2*-0.5 mm from Merck, eluting with a mixture of chloroform and methanol 9:1. The uniform fractions are combined and evaporated to obtain 6.8 g (72.7°/theoretical yield) of 6-ethoxy-2-piperazine-4-thiomorpholinopyrimidine. Example R. 5-carbamoyl-2,4,6-trihydroxy-pyrimidine. This compound is prepared by the method of H. C. Scarborough, W. A. Gould, J. Org. Chem. 26, 3720 /1961/ M from barbituric acid and urea /3 hours at 160°C/. The product with a melting point of 350°C is obtained with a yield of 87.7%. In an analogous manner, 5-carbamoyl-4,6-dihydroxy-2-thiopyrimidine is obtained from thiobarfurous acid and urea (3 hours at 170°C). Example S. 5-carbamoyl-4,6-dihydroxy-2-methylthiopyridine. To a solution of 4.2 g (0.105 moles) of sodium hydroxide in 150 ml of water is added 5.6 g (0.03 moles) of 5-carbamoyl-4,6-dihydroxy-2-thiopyrimidine, then 4.7 g (0.03 moles) of methyl iodide is added while stirring at room temperature and the mixture is then stirred for 3 hours. The resulting mixture is acidified, the precipitated 5-carbamoyl-4,6-dihydroxy-2-methylthiopyrimidine is filtered off and recrystallized from dioxane. 1 g (16.6% of theory) of a product melting at 360°C is obtained. Example T. 5-cyano-2,4,6-trichloropyrimidine. This compound is prepared from 5-carbamoyl-2,4,6-trihydroxypyrimidine, phosphorus oxychloride, by reaction at 100°C for 18 hours [see C. A. 62, 7775 (1965/). The product, recrystallized from petrol (boiling point 100-140°C), melts at 123°C, and the reaction yield is 65% of the theoretical. In an analogous manner, 5-cyano-4,6-dihydroxy-2-methylthiopyrimidine, phosphorus oxychloride and diethylaniline are prepared by boiling under reflux from 5-carbamoyl-4,6-dihydroxy-2-methylthiopyrimidine, melting point 107°C (from petrol). Example U. 4,6-Dihydroxy-5-formyl-2-methylthiopyrimidine. This compound is prepared by stirring for 4 hours at 0°C. 4,6-dihydroxy-5-formyl-2-phciopyrimidine with methyl iodide in an aqueous solution. The product melts at 250°C and the yield is 97.8% of the theoretical yield. Example V. 4,6-dichloro-5-dichloromethyl-2-methylthiopyrimidine. 121 g (0.58 mol) of 4,6-dihydroxy-5-formyl-2-mdtylthiopyrimdine are carefully treated with 600 ml of phosphorus oxychloride and after the turbulent reaction has stopped, 80 µl of diethylaniline are added. The mixture was heated under reflux for 6 hours, then the excess phosphorus oxychloride was distilled off under reduced pressure, the residue was carefully treated with ice and extracted with chloroform. The extract was washed with water, dried and evaporated under reduced pressure to dryness. The residue was recrystallized from petrol with activated charcoal added, yielding 70 g (43.3%) of theory of 4,6-dichloro-5-dichloromethyl-2-methylthiopyrimidine, melting point 66°C. Example W. 6-Ethoxy-5-formyl-2-methyl-3-dimethyl-4-thiomorpholinopyrimidine. To a solution of 11.4 g (0.041 mole) of 4,6-dichloro-5-dichloromethyl-2-methylthiopyrimidine in 100 ml of ethanol was added dropwise, with stirring and ice-cooling, a solution of sodium ethoxide prepared from 0.95 g of methylthiopyrimidine. g (0.041 mol) of sodium and 50 ml of ethanol. The mixture was stirred for 1 hour, then water was added and the mixture was extracted with chloroform. The chloroform was evaporated from the extract, the residue was dissolved in dioxane and, with stirring and cooling, 31 g (0.3 mol) of thiomorpholine was added and the mixture was left overnight at 20°C. The mixture was then diluted with water, extracted with chloroform, the extract was washed with water, dried, and the chloroform was evaporated. The residue was purified by chromatography on a Merck silica gel column, 0.2-0.5 mm, eluting with a petrol-ethyl acetate mixture:1. The uniform fractions are evaporated to dryness and the residue is recrystallized from gasoline, obtaining 5.6 g (45.6° (theoretical yield)) of 6-etho'oxy-1-phonyl-2-methylthio-4-tdomorphoHnopyrimdine. Product analysis. Formula C12H17N^OgS2> molecular weight 299.42. Calculated: 48.14% C, 5.72% H, 14.03% N. Found: 48.45% C, 5.82% H, 13.78% N. In an analogous manner, from 4,6-dichloro-5-dichloromethyl-2-methylthiopyrimidine, sodium ethoxide and 1-oxydothiomorpholine there is obtained 6-ethoxy-5-formyl-2-methylthio-4-(1-oxidothiomorpholine)-pyrimidine, which, when recrystallized from ethyl acetate with dioxane, melts at 180°C. Example X. 5-Carboethoxy-2,4-dihydroxy- pyrimidine. This compound is produced from the ethoxymethylene ester of malonic acid and urea. The product melts at a temperature of 241-243°C. The following compounds are prepared in a similar manner: a) 5-carboethoxy-4-hydroxy-2-morpholinopyrimidine is prepared from the ethoxymethylene ester of malonic acid and morpholinoguanidine, which melts at 164-166°C, b/ 5-carboethoxy-4-hydroxy-2-thiomorpholinopyrimidine is obtained from ethoxymethylene malonate ester and thiomorpholinoguanidine, which, after recrystallization from ethanol, melts at 133^165°C. Example Y. 5-canboethoxy-2-chloro-4-thio- morpholinopdrimidine. 4 g (0.018 mol) of S-carboethoxy-E^-dichloropyrimidine, obtained by the method of A. Dornów, G. Petsch [Diebigs Ann. Chem. 588, 45-^61 (1954),] was dissolved in 70 ml of ice-cold ethanol and, while stirring at 0°C, treated with a solution of 4.1 g (0.036 mol) of thiomorpholine. The thick crystalline mass formed was stirred for 15 minutes, then poured into 150 ml of water, the crystals were filtered off and washed with water. Obtains 4.8 g (92.3°/theoretical yield) of 5-carboethoxy-2-chloro-4Hthiomorpholinopyrimdine with a melting point of 7K)-1710C. Product analysis. Formula C11H1^ClN3OS, molecular weight 287.75. Calculated: 45.91% C, 4.90% H, 14^60% N. Found: 46.10% C, 5.06% H, 14.66% N. The following compounds are prepared in a similar way: a/ z from 5-carboethoxy^2,4-dichloropyrimidine i 1-oxidothiomorpholine, 5-carboethoxy-2-chloro-4-(1-oxidothiomorpholino)-pyrimidine with a melting point of 123-126°C (from butanol with 40 cyclohexane) and c) from 5-carboethoxy-2,4-dichloro-6-methylpyrimidine, prepared by a method analogous to that described by A. Dornów, G. PetsCh, Liebigs Ann. Chem. 588, 45^61 (1954) with 5-carboethoxy-2,4-dihydroxy-45-6-methylpyrimidine and phosphorus oxychloride with phosphorus pentachloride [R. W. Lamon, J. Het. Chem. 6, 2611-264 /1969/], by reaction with 1,1-dioxydothiomorpholine, 54Larboethoxy-2-chloro-4-(1,1-dioxydothiomorpholino/J6-methylpyrimidine 50) is obtained, melting point 145-148°C. Example Z. 5Jcarboethoxy-4-chloro-2-mor- phoMnopyrimidine. 14.4 g (0.057 mol) of 5-carboxy-4-hydroxy-2-morpholinopyrimidine are added to a mixture of 100 ml of phosphorus oxychloride and phosphorus pdeciocMide and refluxed for 20 minutes, resulting in a clear solution. Excess phosphorus oxychloride is distilled from this solution, the residue is carefully treated with ice-cold water and slightly alkalinized with sodium bicarbonate, then the obtained crystals are filtered off and recrystallized from ethanol, obtaining 5-carboethoxy-4-cMoro-2-morpho-inopyrimidine with a melting point of 79-60.5°C. 65 In an analogous manner, Skarboethoxy-17 to 115 18 xy-2-thiomorphoylmopyrimidine and phosphorus oxychloride with phosphorus pentachloride produce Skartoo-ethoxy-4-cMoro-2-thiomorphoylmopyrimidine with a melting point 81-83°C (from ethanol). The method according to the invention is illustrated in the following examples. Example I. 6-methyl-4-morpholino-5-nitro-2-piperazine-ipdrimidine. To a solution of 19.4 g (0.1 mol) of piperazine hexahydrate in a solution cooled to a temperature of about 5°C. 300 ml of a 1:1 mixture of acetone and dioxane a solution of 2.6 g (0.01 mol) obtained from 2,4-dichloro-6-matyl-5-nitropdrimidine and morpholine 2-cMoro-6-methyl-4-morpholino-5-nitropyrimidine (melting point 127-1290°C) in 100 ml of acetone mixture was added dropwise with stirring and cooling with dioxane 1:1. After about 1 hour, the solvents are distilled off under reduced pressure, the residue is mixed with about 100 ml of water, the precipitate is filtered off, washed with water and dried, obtaining 3.0 g (97% of theoretical yield) of 6-methyl-4-morpholino-5-nitro-2-piperazinopyrimidine. After semi-reprecipitation with 2 N ammonium hydroxide from a solution in about 0.2 N hydrochloric acid, the product melts at 143-145°C. Analysis: Formula C^Ha^N^O^ (308.3%). Calculated: 50.65% C, 6.55% H, 27.21% N. Found: 50.70% C, 6.74% H, 27.55% N. Example 2 6-Methyl-5-nitro-2-piperazine-4-thiomorpholinopyrimidine. This compound is prepared in a manner analogous to that described in Example 1, from 2-chloro-6-methyl-5-nitro-4-thiomorpholinopyrimidine (mp 106-108°C) and piperazine. The product recrystallized from ethyl acetate melts at a temperature of 141-143°C. Example III. 6-methyl-5-nitro-'2!-piperazine-4-(1-oxidothiomorpholino)-pyrimidine. This compound is prepared in a manner analogous to that given in Example I, from 2-chloro-6-methyl-5-nitro-4-(1-oxidothiomorpholino)-pyrimidine (melting point 1471-150°C) and piperazines. The product melts at 17-6-178°C (from ethyl acetate). Example IV. 5-nitro-2-piperazine-4-(l-oxy- dotdomorpholino)-pyrimidine. This compound produces. by a method analogous to that described in Example 1, from 2-chloro-5-nitro-4-(1-oxidothiomorpholine)-pyrimidine (mp 155-157°C) and piperazine. The product melts at 135-145°C. Example 5: 6-Ethyl-4-immorpholino-5-nitro-2-piperazinopyrimidine. This compound is obtained by a method analogous to that described in Example 1, from 6-ethyl-2-chloro-4-morpholino-5-nitropyrimidine (mp 87-88°C) and piperazine. The product melts at 107-145°C. <109°C. Example VI. 6-ethyl-5-nitro-2-piperazine-4-thiomorpholinopyrimidine.' This compound is prepared in a manner analogous to that described in Example 1, from 6-ethyl-2-chloro-5-nitro-4-tdomorphoinopH'ymidine (melting point 12-73°C) and piperazine. The product melts at a temperature of 111-113°C. Example VII. 6-ethyl-5-nitro-2-piperazine-4-(1-oxidothiomorphomorpholino)-pyrimidine. This compound is prepared in a manner analogous to that described in Example 1, from 6-ethyl-2-chloro-5-nitro-4-(1-oxidothiomorphomorpholino)-pyrimidine (melting point 137-138°C and piperazine. The product melts at 176-178°C. Example VIII. 5-nitro-2-piperazine-6-propyl-4-thiomorphendopyrimidine. . 10 This compound is prepared in a manner analogous to that described in Example 1, from 2-chloro-5-nitro-6-propyl-4-thiomorpholinopyrimidine, having the consistency of a piperazine resin. The product melts at a temperature of 140°-42°C. Example 9. 5-nitro-2-piperazine-6-propyl-4-(1-oxydothiomorpholine)pyrimidine. This compound is obtained in a manner analogous to that described in Example 1, from 2-cichloro-5-nitro-6-propyl-4-(1-oxydothiomorpholine)pyrimidine (melting point 108-111°C/piperazine. The product melts at 208-210°C (from methanol). Example X. 6-Isopropyl-5-nitro-12-piperazine-4-(1-oxidothomorpholino)-pyrimidine. This compound is prepared in a manner analogous to that given in Example I, from 2-chloro-6-isopropyl-5-nitro-4-(1-oxidothomorpholino)-pyrimidine (mp. 140-142°C) and piperazine. The product melts at 175-178°C (from methanol). Example XI. 6-tertiary-butyl-5-nitro-2-piperazine-4-(1-oxidothiomorpholino)-pyrimidine. This compound is prepared in a manner analogous to that described in Example 1, from 6-tertiary-butyl-2-chloro-5-nitro-4-(1-oxidothiomorpholino)-pyrimidine (melting point) 155-57°C/ d piperazine. The product melts at a temperature of 185°C (from methanol). Example XII. 2-(N-carboethoxypiperazine) 40-6-methyl-5-nitro^-Zl-ofk^sydothiomonfolino(^pyrimidine). This compound is prepared in a manner analogous to that described in Example 1, from 2-chloro-6-methyl-5-niitro-4-(l-oxidothiomoTfolino/Hpyrimidines /temperature melting point 147-150°C/ and 'N-carboethoxypiperazine. The product melts at a temperature of 150°C. -152°C (from ethyl acetate). Example XIII. 2-(N-formyl-dperazino)-6-methyl 5-nitro-4-(1-oxydothiomorphalno)-pyrididine-. This compound is obtained in a manner analogous to that described in Example 1, from 2-chloro-6-methyl-5-nitro-4-(1-oxidothiomorpholino)-pyrimidine (mp. 147-150°C) and N-formylpiperazine. The product melts at 202-2104°C (from ethyl acetate). Example 14. 4-(N-formylpiperazine)-6-methyl-6-nitro-2-(1-oxidothiomorpholino)-pyrimidine. The phen compound is prepared in a manner analogous to that described in Example 1, from 2-chloro-4-(NHphosylpiperazine)-6-methyl-5-nitropiximidine (melting point 163-165°C) and 1-oxidized monofold. The product recrystallized from water melts at 155-158°C.93 115 19 Example XV. 6-Methyl-5-nitro-4-piperazino[2-](1-oxidothiomorpholino)-pyrimidine. This compound is prepared from 4-(N-formylpiperazino)[6-]methyl-5-nitro-2-(1-oxidothiomorpholino]-pyrimidine (mp 155-158°C) by refluxing with sodium hydroxide in methanol for several hours. The product melts at 17-180°C (from water). - Example XVI. 5-Nitro-2-piperazine-4-(1-oxydothiomorphine)-6-pyrimidinecarboxylic acid methyl ester. This ester is prepared in a manner analogous to that described in Example 1, from 2-chloro-5-nitro-4-(1-oxydothiomorphine)-6-pyrimidinecarboxylic acid methyl ester (mp 164-165°C) and piperazine. The product, recrystallized from methanol, melts with decomposition at < temperature 196—180C. Example XVII. 5-nitro-2-piperazine-4-/l-acid ethyl ester <)Ixidothiomorpholino/6L-pyrimidinecarboxylic acid. This compound is prepared in a manner analogous to that described in Example 1.1 from 2-chloro-5-nitro-4-(1-oxidothiomorpholino)-6-pyrimidinecarboxylic acid ethyl ester (mp 128-130°C) and piperazine. The product melts at 173-175°C. - ? Example XVIII. 5-Chloro-2-piperazine-4-(1-oxidothiomorpholino)-6-pyrimidinecarboxylic acid nitrile. To a solution of 19.4 g (0.1 mole) of piperazine hexahydrate in 100 ml of dioxane is slowly added 0.8 g (0.02 mole) of 2,5-dicichloro-4-(1-oxidothiomorpholino)-6-pyrimidinecarboxylic acid nitrile, melting at 145°-147°C, prepared from 2,4,5-trichloro-4-pyrimidinecarboxylic acid nitrile and 1-oxidothiomorpholine. The mixture warms slightly during the addition and a solution is rapidly formed. After standing for a short time, the mixture was evaporated in vacuo to almost dryness and the residue was stirred with about 100 ml of water. The faintly yellowish precipitate was filtered off, rinsed with water and dried, yielding 6.4 g (94% of theory) of chloro-2-piperazine-4-(1-oxidothiomorpholino)-6-'-pyrimidinecarboxylic acid nitrile, mp 203-205°C. The product reprecipitated with ammonia from a solution in about 0.2 N hydrochloric acid melts at 206^208°C. Analysis of the product: Formula C13H17NdOSCl /340.8/. Calculated: 45.81% C, 5.03% H, 9.41% S, 10.40% Cl. Found: 45.50% C, 5.04% H, 0.45% S, 10.60% Cl. The same compound is prepared from 5-chloro-2-piperazine-4-thiomorpholine-6H-pyrimidinecarlboxylic acid nitrile hydrochloride /melts . with: symptoms of decomposition at a temperature of 297—299°C/ by oxidation with sodium metaperiodate in an aqueous medium.' *"'¦•¦ Example XIX. 5-Chloro-2-piperazine-4-thiomorpholino-6-pyrimidinecarboxylic acid nitrile. .-..,.... This compound is prepared in a manner analogous to that described in Example I, from 2,5-dichloro-4-thiomorpholino-6-pyrimidinecarboxylic acid nitrile (melting point 126-127°C) and piperazine. The product melts at 137-140°C. By recrystallizing the nitrile from 0.1 N hydrochloric acid, the hydrochloride of this nitrile is obtained, melting point 2697-299°C (decomposition). Example XX. 5-Chloro-2-piperazine-4-(1,1-dioxidothiomorpholino)-6-pyrimidinecarboxylic acid. To a solution of 2.5 g (0.03 mole) of piperazine in 50 ml of dioxane is slowly added 1.8 g (0.005 mole) of 2-ethylsulfonyl-5-chloro-4-(1,1-dioxidothiomorpholino)-6-pyrimidinecarboxylic acid nitrile, m.p. 234°-237°C, obtained from 2-ethylthio-5-chloro-4-thiomorpholino-6-pyrimidinecarboxylic acid nitrile by oxidation with potassium permanganate in dilute hydrochloric acid. After standing for a short time, the solution is evaporated to almost The residue is then stirred in vacuo and the precipitate is filtered off, washed with water and dried. 1.4 g (78% of theory) of 5-chloro-2-piperazine-4-(1,1-dioxide-dothiomorpholino)-6-pyrimidinecarboxylic acid nitrile is obtained, which after recrystallization from a mixture of methanol and dioxane 9:1 melts at 235-237°C. Analysis of the product: Formula C13HirN6O2SOi (356.8). Calculated: 43.76% C, 4.80% H, 23.55% N, 9.94% Cl. Found: 43.90% C, 4.83% H, (23.40% N, 10.00% Cl. The same compound is also obtained from 2,5-dichloro-4-(1,1-dioxidothiomorpholino)-6-pyrimidinecarboxylic acid nitrile (m.p. 198-199°C) by reaction with piperazine in a manner analogous to that described in Example 18. Example 21. 5-Chloro-2-piperazine-4-thiomorpholino-6-pyrimidinecarboxylic acid nitrile hydrochloride. 1.0 g (0.003 mole) of 5-chloro-2-phenoxy-4-thiomorpholino-6-pyrimidinecarboxylic acid nitrile, m.p. 112-114°C, obtained from 2,5-dichloro-4-(1,1-dioxidothiomorpholino)-6-pyrimidinecarboxylic acid nitrile (m.p. 112-114°C), 2,5-dichloro-4-thiomorpholine-6-pyrimidinecarboxylic acid and sodium phenoxide in phenol are heated together with 1.3 g (0.015 mole) of piperazine in 50 ml of dioxane at about 50°C for 4 hours, then evaporated under reduced pressure to a small volume and the residue is stirred with about 40 ml of water, the precipitate is filtered off, washed with water and dried. 0.7 g of 5-chloro-2-piperazine-thiomorpholine-C-pyrimidinecarboxylic acid nitrile hydrochloride is obtained, which is 72% of the theoretical yield. After recrystallization from 0.1 N hydrochloric acid, the product is Melts with symptoms of decomposition at 2B7-299°C. Analysis of the product: Formula C13H17Ne9Cl.HCl (361.3%). Calculated: 23.26% N, Found: 23.62% N. This product is obtained in an analogous manner from nitrile (2-ethylthio-6-chloro-4-thiomorpholino-6-pyrimidinecarbaxylic acid [m.p. 115-117°C], melting at reflux with piperazine in dioxane for about 8 hours. Example XXII. 5-Chloro-2-piperazine-4-(1-oxo-thiomorpholino)-6-pyrimidinecarbaxylic acid nitrile 0.3 g (0.001 mole) of 5-chloro-4-phenoxy-2-piperazine-6-pyrimidinecarboxylic acid nitrile, melting at 126-128°C, obtained by reacting 2,5-dichloro-4-phenoxy-epyrimidinecarboxylic acid nitrile with piperazine in a cooled 1:1 mixture of acetone and dioxane, is heated with 2.4 g (0.02 mole) of 1-oxydothiomonfoline at about 140°C for 90 minutes, after which the dark-colored melt obtained is stirred with a small amount of water and the precipitated crude product is purified on silica gel, eluting with a mixture of methanol and concentrated ammonium hydroxide 8:1. The pure product is precipitated with ammonia from a solution in 0.2 N hydrochloric acid, yielding 5-chloro-2-piperazine-4-(1-oxidothiomorpholino)-6-pyrimidinecarboxylic acid nitrile, melting point 206-208°C. Example XXIII. 5-Bromo-2-piperazine-4-thiomorpholino-6-pyrimidinecarboxylic acid nitrile hydrochloride. This compound is prepared in a manner analogous to that described in Example XVIII from 5-bromo-5-chloro-4-thiomorpholino)-6-pyrimidinecarboxylic acid nitrile (melting point 138-142°C) and pyridine. By dissolving this nitrile in acetone, Sinking and acidifying with an alcoholic solution of hydrochloric acid, the hydrochloride of this nitrile is obtained, melting with symptoms of decomposition at 245-247°C. Example XXIV. 5-Formo-2-piperazine-4-(1-oxidothiomorpholino)-6-pyrimidinecarboxylic acid nitrile. This compound is prepared in a manner analogous to that described in Example XVIII from 5-bromo-2-chloro-4-(1-oxidothiomorpholino)-6-pyrimidinecarboxylic acid nitrile (mp -180-182°C) and piperazine. The product, recrystallized from acetone, melts at 180-185°C. Example XXV. 5-methyl ester -chloro-2-diperazine-4-(1-oxidothiomorpholino)-6-pyrimidinecarboxylic acid. This compound was prepared in a manner analogous to that described in Example 18 from 2,5-dichloro-4-(1-oxidothiomorpholino)-6-pyrimidinecarboxylic acid methyl ester (m.p. 140-142°C) and piperazine. The product melts at 160-170°C. Example 26. 5-Bromo-2-piperazine-4-(1-oxidothiomorpholino)-6-pyrimidinecarboxylic acid methyl ester ... 5-bromo-2-chloro-4-(1-oxidothiomorpholino)-6-pyrimidinecarboxylic acid (m.p. 166-168°C) and piperazine. The product melts at 160-163°C. Example XXVII. 6-Methyl-4-(2-piperazine-2-(1-oxidothiomorpholino)-5-pyrimidinecarboxylic acid nitrile. 2.7 g 1/k), 0.1 moles. 4-Chloro-6-methylnitrile. <-2-(1-Oxidothiomorpholino)-5-pyrimidinecarboxylic acid, melting at 251°-253°C, obtained by the reaction of 2,4-dichloro-6-methyl-5-pyrimidinecarboxylic acid nitrile and 1-oxidothiomorpholine in cold acetone, is mixed with a solution of 8.6 g (0.1 mole) of piperazine in 80 ml of dioxane and boiled under reflux for 30 minutes, after which the main part of the solvent is distilled off under reduced pressure. The residue was stirred with approximately 80 ml of water and a small amount of 8 N sodium hydroxide added, whereupon the reaction product separated, which was initially unctuous but quickly solidified as a precipitate. The precipitate was filtered off, washed with water, and dried, yielding 2.8 g of 6-methyl-4-piperazine-2-(1-oxidothiomorpholino)-5-pyrimidinecarloxylic acid nitrile (87% of theory). After dissolving in about 0.2 N hydrochloric acid, precipitating with 2 N sodium hydroxide and recrystallizing from water, there is obtained 1.9 g (59%) of theoretical yield of product, melting point 215-216°C. Analysis of the product: Formula - C^H^OS (320.4). Calculated: 52.48% C, 6.29% H, 26.23% N, 10.01% S. Found: 52.10% C, 6.26% H, 26.05% N, 10.01% S. Example XXVIII. 5-Chloro-[6-methyl-2,-piperazine-4-(1-oxidothiomorpholino)-pyrimidine. This compound is prepared in a manner analogous to that described in Example XXVII from 2,5-dichloro-[6-methyl-4-(1-o-oxidothiomorpholino)-pyrimidine (mp. 125-130°C)) and piperazine. The product melts at 163-165°C (from ethyl acetate). Example XXIX. 5-ibromo-6-methyl-4-morpholino-2-piperazinopyrimidine. This compound is prepared in a manner analogous to that described in Example XXVII, from 5Hbromo-2-chloro-6-methylD-4-morpholinopyrimidine (melting point 98-100°C) and piperazine. Product 45 melts at 86— <90°C Example XXX. 5-bromoJ6-methyl-2-piperazine-4-thiomorpholinopyrimidine. This compound is prepared in a manner analogous to (described in Example XXVII, from 5-bromo-2-50-chloro-6methyl-4-thiomorpholinopyrimidine (melting point 1125-126°C) and piperazine. The product melts at 1111-T12°C. Example XXXI. 5-bromo-2-chloro-6-methyl-4-(1-oxydotibmortfolino)-pyrimidine. This compound is prepared in a manner analogous to that described in Example XXVII from 5-bromo-2-chloro-6-methyl-4-(1-oxidothiomortfolino)-pyrimidine. melting 128-130°C (and piperazine. The product melts at 158-160°C. eo Example XXXII. 6-methyl-2-^piperazine-4-thiomorpholino-5-pyrimidinecarbioxylic acid nitrile. 2.7 g (0.101 mol) of 4-chloro^2-(N-) nitrile -formylpiperazine-6-methyl-5-pyrimidinecarboxylic acid, melting point 102-194°C, obtained by reacting 2,4-di-chloro-6-methyl-5-pyrimidinecarboxylic acid nitrile with N-formylpiperazine in an acetone medium and with cooling, mixed with 2.1 g (0.02 mole) of thiomorpholine in 60 ml of dioxane and boiled under reflux for about 1 hour. The solvent was then distilled off under reduced pressure and the residue was boiled under reflux for 30 minutes with the addition of about 60 ml of dipropanol in the presence of sodium hydroxide. The solvent was then evaporated under reduced pressure, the residue was dissolved in dilute hydrochloric acid and 6-methyl-2-piperazine-4-thiomorpholine-5-pyrimidinecarboxylic acid nitrile was precipitated with concentrated ammonium hydroxide. The product was recrystallized from a 1:1 mixture of methanol and water, melting at temperature 146-1'48°C. 1.6 g of product are obtained, which is 53% of the theoretical yield. Product analysis: Formula -C^a^S /304.4/. Calculated: 55.24% C, 6.62% H, 27.61% N, 10.54% S. Found: 55.35% C, 6.57% H, 27.43% N, 10.50% S. Example XXXIII. 6-methyl-5-nitro-2-piperazine-4-i(yl,1-dioxidot,iomorpholino)-pyrimidine. Add 1.6 g /0.005 mole of 6-methyl-5-nitro-i2-pipera- to the solution cooled to a temperature of about 5°C. [6-methyl-5-nitro-2-piperazine-4-[1,1-dioxydothiomorpholino-pyrimidine] (melting point 141-143°C) in about 60 ml of 0.5 N hydrochloric acid. A solution of 0.8 ± 0.005 mol of potassium permanganate in 310 ml of water was slowly added dropwise with cooling and stirring. The mixture was then stirred for 1 hour at about 5°C. The manganese dioxide that had separated was then removed with sodium bisulfite solution. Concentrated ammonium hydroxide was added to the resulting solution, the precipitated product was filtered off, washed with water and dried, yielding 1.4 g (79% of theory) of [6-methyl-5-nitro-2-piperazine-4-[1,1-dioxydothiomorpholino-pyrimidine] melting point 208-211°C. After repeated precipitation with ammonia from a solution in 0.1 N hydrochloric acid, the product melts at 21 <1^213°C. Product analysis. Formula ClsH2iNtfO4S /356.4/. Calculated: 42.81% C, 5.66% H, 0.00% S. Found: 43.60% C, 5.74% H, 9.06% S. Example XXXIV. 5-Acetyl-2-piperazine-4-(1-oxidothiomorpholine)-pyrimidine. This compound is prepared in a manner analogous to that described in Example 1 from 5-acetyl-2-chloro-4-(1-oxidothiomorpholine)-pyrimidine (melting point 168-169°C) and piperazine. To isolate the pure product, the crude product is stirred with water, a small amount of insoluble material is filtered off, sodium hydroxide is added to the filtrate, and the mixture is extracted with chloroform. The extract is dried, the solvent is distilled off, and the residue is recrystallized from ethyl acetate, yielding a product with a melting point of 140-145°C. Example XXXV. 2-Formylpiperazine-4-thiomorpholino-chloropyrimidine, 1115 24 125.1 g of 4-thiomorpholino-2,6-dichloropyrimidine, m.p. 118.5-121.5°C, are dissolved in 1.2 liters of dioxane, treated with a solution of 125.6 g of N-monoformylpiperazine in 0.1 liter of dioxane and boiled under reflux for 2 hours. The precipitated N-monoformylpiperazine hydrochloride is then filtered off, the filtrate is diluted with 2 liters of water and cooled in an ice bath. The precipitated white crystalline 2-formylpiperazine-4-thio;morpholino-6-chloropyrimidine is filtered off, washed with a small amount of 50% dioxane and dried at 100°C, obtaining 146 g (90% of theoretical yield) of the product, melting at 195°C! 9i80C.Example XXXVI. 2-piperazine-4-thiomorpholino-5-nitro j6-cyclohexyl-aminopyrimidine dihydrochloride. 3.0 g of 2-methylmercapto-4-thiomorpholino-5-nitro-6-cyclohexylaminopyrimidine, melting point 145-146°C, is mixed with 8.0 g of anhydrous piperazine and heated at 130°C for 1 hour. The resulting melt is diluted with 510 ml of water, causing the precipitation of a resinous product which crystallizes on trituration with acetone. This product is dissolved in acetone, filtered with activated charcoal, and acidified with ethereal hydrochloric acid to obtain a precipitate of 2-piperazine-4-thiomorpholino-5-nitro-6-cyclohexylaminopyrimidine dihydrochloride. 2.6 g of product (64.5% of theory) is obtained, which melts with symptoms of decomposition at 173°C. Example XXXVII. 2-Formylpiperazine-4-(1-oxidothiomorpholino)-5-nitro-6-chloropyrimidine diethyl ester. To a suspension of 1.44 g of sodium hydride in 20 ml of anhydrous dioxane is added dropwise with stirring a solution of 10.8 g of sodium hydride in 12 ml of dioxane, and then a hot solution of 5.84 g of 2-formylpiperazine-4-(1-oxidothiomorpholino)-5-nitro-6-chloropyrimidine in 95 ml of dioxane is added, whereupon the sodium salt of 2-formylpiperazine-4-(1-oxidothiomorpholino)-5-nitro-6-chloropyrimidine diethyl ester is immediately formed in the form of a mass of 1.44 g. This salt was dissolved in 100 ml of petroleum ether, the precipitate was allowed to settle and filtered off, then dried, dissolved in 50 ml of water, neutralized with 2 N hydrochloric acid and extracted with a mixture of chloroform and methanol 2:1. The extract was evaporated, yielding 6.9 g (788.0% of theory) of 2-formylpiperazine-4-(1-oxidothiomorifolino)-5-nitropyrimidicHS-malonic acid diethyl ester as a yellow resinous product. Examination by thin-layer chromatography on a silica gel plate using as eluent a mixture of benzene, ethanol and concentrated ammonium hydroxide in the ratio 75:25:1 shows that product 60 is a homogeneous substance, Rf = 0.55. Example XXXVIII. 2-Pyperazine-4-(1-oxydothiomorpholino)-5-nitropyrimidyl-6-malonic acid ethyl ester. 5.8 g of sodium are dissolved in 100 ml of anhydrous ethanol, 4.35 g of 2-formylpiperazine-4-(1-oxidothiomorpholino)-5-nitropyrimidyl-6-malonic acid diethyl ester (see Example XXXVI) are added and the dark red solution is boiled under reflux for 1.5 hours, then the ethanol is distilled off, the residue is stirred with ice-cold water and extracted with ethyl acetate. The solvent was evaporated from the extract, leaving a resinous residue of 2-piperazine-4-(1-oxidothiomorpholino)-5-nitropyrimidyl-6-acetic acid ethyl ester, 1.2 g (34% of theory). Thin-layer chromatography on a silica gel plate using a mixture of benzene, ethanol and concentrated ammonium hydroxide 75:25:1 as eluent showed the product to be homogeneous, Rf = 0.4. Example XXXIX. 2-Piperazine-4-(1-oxidothiomorpholino)-5-nitropyrimidyl-6-malonic acid diethyl ester, hydrochloride. 2.95 g of 2-formylpiperazine-Z-oxidothiomorpholino-Z-ditropyrimidyl-6-malonic acid diethyl ester was dissolved in a mixture of 75 ml of ethanol and 75 ml of a saturated ethanolic solution of hydrochloric acid and allowed to stand at room temperature for 24 hours. The solvent was then distilled off at room temperature under reduced pressure and the crystalline residue was recrystallized from ethanol. 1.57 g (52.3%) of theoretical yield of product was obtained, melting with symptoms of decomposition above 335° C. Thin-layer chromatography as described in Example XXXVIII showed that the hydrochloride obtained was a homogeneous product, iRf = 0.25. Analysis of product: Formula C19H29CINS07 (521.00). Calculated: 43.80% C, 5.01% H, 16.13% N, 6.81% Cl. Found: 43.80% C, 5.69% H*, 15.87% N, 6.97% Cl. Example 41. 2-1-Formylpiperazine-4-/1-oxo-dothiomorpholinoZ-S-nitro-e-methylmercaptopyrimidine. 0.27 g of sodium metal is dissolved in 15 ml of ethanol and the solution is saturated with methyl mercaptan, passing nitrogen through the vessel as a protective gas. A solution of 2-formylpyrazine-4-(1-oxidothiomorpholino)-5-nitro-6-chloropyrimidine in a mixture of 20 ml of ethanol and 20 ml of dioxane, heated to approximately 80°C, was then poured into the solution, immediately forming a precipitate of sodium chloride. To complete the reaction, the mixture was stirred for another hour, then the solvent was distilled off, the residue was stirred with water, and extracted three times with chloroform. The extract was dried over sodium sulfate, the chloroform was evaporated, and the viscous yellow residue was crystallized from ethyl acetate. 2.5 g (82.5% of theoretical yield) of 2-formylpiperazine-4-(1-oxidothiomorpholino)-5-nitro-6-methylmercaptopyrimidine with a melting point of 238°C are obtained. Example 11. 2-piperazine-4-(1-oxidothiomorpholino);-5-nitro-6-methylmerlkaptopyrimidine. 1.8 g of 2-formylpiperazine-4-(1-oxidothiomorpholino)-15-nnro-6-methylmercaptopyrimidine. with a melting point of 168-173°C and 50 ml of 2N hydrochloric acid are heated in a steam bath for 45 minutes, then cooled to room temperature, treated until saturation with anhydrous potassium carbonate and extracted with chloroform. The extract is dried over potassium carbonate, the solvent is distilled off and the residue is recrystallized from ethanol to obtain 0.6 g (36.1% of theoretical yield) of melting point 230°C. Example XLII. 2-foTmylopiperazine-4-(l-oxydothiomorpholino/-5-nitro-6-ethylmericaptopyrimidine. This compound is prepared in a manner analogous to that described in Example 176-178°C/ and ethyl mercaptan. The product melts at a temperature of 168-173°C and the yield is 63% of the theoretical yield. Example XLIII. 2-:piperazine-4-(1-oxydothiomorpholino/-5-nitro-6-ethyro,mercaptopyrimids.na. This compound is prepared in a manner analogous to that described in Example salt. The product melts at a temperature of 225-12-28°C, the yield is 67% of the theoretical yield. Example XLIV. 2-Formylpiperazine-4-(1-oxidothiomorpholino)-5-nitro-6-mercaptopyrimidine. This compound is prepared in a manner analogous to that described in Example 40, from 2-formylpiperazine-4-(1-oxidothiomorpholino)-5-nitro-6-chloropyrimidine, melting point 176-178°C, and hydrogen sulphide. The product melts, with symptoms of decomposition, above 240°C, and the yield is 87% of theory. Example 46. 2-Formylpiperazine-4-(1-oxidothiomorpholino)-5-nitro-6-n-propylmercaptopyrimidine. 1.9 g of 2-formylpaparazine-4-/1-oxidothiomorpholino-Z-S-nitro-ε-marcaptopyrimidines, melting with symptoms of decomposition at 240°C, was dissolved in 30 ml of methanol and treated with 0.7 g of potassium methoxide. Then 1.2 g of n-propyl bromide was added and stirred at room temperature for 5 hours. The mixture was then diluted with 100 ml of water and extracted with chloroform. The extract was dried over sodium sulfate and evaporated, leaving a viscous residue which did not crystallize. 1.5 g (71% of theoretical yield) of 2-formyl-piperazine-4-1-1-oxydolthiomorpholino/-5-nitro-6-n-propylmercaptopyrimidine are obtained. Example XLVI. 2-piperazine-4-(1-oxidothiomorpholino)-5-nitro-6-n-propylmercaptopyrimidine. This compound is prepared in a manner analogous to that described in Example 2 N hydrochloric acid. The product melts at 147-150°C, the yield is 62% of the theoretical yield. Example XLVII. 2-formylpiperazine-4-(1-oxydothiomorpholino/-6-nitro-6-allylmercaptopyry- 65 midine.27 93 115 28 This compound is prepared in a manner analogous to that described in Example captopyrimidine and allyl bromide. The product in the form of a non-crystallizing, viscous resin was obtained with a yield of 94% of the theoretical yield. Example XLVIII. 2-piperazine-4-(l-oxydo-thiomorpholino/-5-ndtro-6-allylO'mercaptopyrimidine. This compound is prepared in a manner analogous to that described in Example 6-allyl-mercaptopyrimidines and 2N hydrochloric acid. The product melts at 139°C and the yield is 45% of the theoretical yield. Example XLIX. 2-formylpiperazine-4-(1-oxidothio,morpholino)-15-nitro-6-cyclohexylamino-pyrimidine. 7.78 g of 2-formylpiperazine-4-(1-oxidothiomorpholine)-5-tritro-6-chloropyrimidine, m.p. 176-178°C, are dissolved in 150 ml of dioxane, 4.35 g of cyclohexylamine are added and boiled for 1.5 hours. The mixture is then cooled, diluted with 200 ml of water and extracted with three 50 ml portions of chloroform. The extract is dried over sodium sulfate, filtered with activated charcoal, evaporated and the residue recrystallized from 150 ml of ethanol. 7.6 g (84.5°/theoretical yield) of 2-formylpipierazine-4-(1-oxidothiomorpholino)-5-:nitro-6-chloropyrimidine with a melting point of 254-257°C are obtained. Example L. 2-pipera-monohydrochloride zyno-4-(1-oxydothio.morpholino/-5-nitro-6-cyclohex! silaminopyrimidines. 1.0 g of 2-formylpiperazine-4-(1-oxidothiomorpholino)-5-nitro-6-cyclohexylaminopyrimidine, m.p. 254-257°C, and 30 ml of 2N hydrochloric acid were heated on a steam bath for 1.5 hours, then filtered and evaporated to dryness. The residue was recrystallized from ethanol, yielding 0.7 g (67% of theory) of product which melted, with symptoms of decomposition, at 273-275°C. Example 11. 2-formylpiperazine-4-(1-oxidothiomorpholino) This compound was prepared in a manner analogous to that described in Example 49, from 2-formylpiperazine. Perazine-4-(1-oxidothiomorpholino)-5-nitro-6-chloropyrimidine, melting point 176°-176°C, and aniline. The product melts at 200°-204°C, the yield being 73.2% of theory. Example LII. 2-Piperazine-4-(1-oxidothiomorpholino)-5-nitro-6-phenylaminopyrimidine* This compound is prepared from 2-formylpiperazine-4-(1-oxidothiomorpholino)-5-nitro-6-phenylaminopyrimidine and 2N hydrochloric acid. The product melts at 235°C, the yield being 46.4% of theory. Example LIIII. 2-formylpiperazine-4-(1-oxido,thiomorpholino/-5-nitro-i6-/4-chlorophenylamino/-pyrimidine. This compound is prepared in a manner analogous to that described in Example melting point 176-178°C from 4-chloroaniline. The product melts at 248°C, the yield is 72.9% of the theoretical yield. Example LIV. 2-piperazine-4^/1-oxidothio,morpholino/-5-nitro-16-/4-chlorophenylamino/-pyrimidine monochloride. This compound is prepared in a manner analogous to that described in example L, from 2-formylpiperazine-4-(1-oxidothiomorpholdrio)-5-nitro-6-(4-chlorophenylamino)-pyrimidine and 2N hydrochloric acid. The product melts with signs of decomposition at a temperature of 300°C and the yield is 53.2% of the theoretical yield. Example LV. 2-formylpiperazine-4-(1-oxydothiomorpholino)-5-nitro-6-(2-kaiiboxy[Penylamino)-pyrimidine. This compound is prepared in a manner analogous to that described in Example XLIX, by the reaction 2-formylpiperazine-4-1-oxydothiomorpholino -5-nitro-6-chloropyrimidines, melting point 176-178°C with anthranilic acid in the presence of a three-fold molar amount of triethylamine. The product melts, with signs of decomposition, at 163-168°C, and the yield is 63% of theory. Example 66. 2-Piperazine-4-(1-oxidothiomorpholino)-5-nitro-6-(2-carboxyphenylamino)-pyrimidine monochloride. This compound is prepared in a manner analogous to that described in Example 9, from 2-formylpiperazine-4-(1-oxydothiomorpholano)-5-nitro-6-(2-carboxyphenylamino)-pyrimidine and 2 N hydrochloric acid solution. The product melts at 290°C, and the yield is 73.4%. Yield: 100% of theory. Example LVII. 2-Piperazine-4-(1-oxidothiomorpholino)-5-nitro-6-(2-carbomethoxyphenylamino)-pyrimidine dihydrochloride. This compound was prepared in a manner analogous to that described in Example XXXIX, by boiling 2-formylpiperazine-4-(1-oxidothiomorpholino)-5-nitro-6-(2-carbomethoxyphenylamino)-pyrimidine with methanolic hydrochloric acid for 3 hours. The product melts, with symptoms of decomposition, at 210°C, and the yield is 53.5% of theory. Example LVIII. 2-formylpiperazine-4-(1-oxydothiomorpholino/-5-nitro-6-(2-pyridylamino)-50-pyrimidine. This compound is prepared in a manner analogous to that described in Example melting point 176-178°C and 55 2-aminopyridine. The product melts at a temperature of 240-243°C and the yield is 52% of the theoretical yield. Example LIX. 2-piperazine-4-/l-o dihydrochloride! fesydothiomorpholino/-5-niitro-6-/2-pyridy- 60 laamino7-pyrimidine. This compound is prepared in a manner analogous to that described in Example XXXIX, from 2-formyl-piperazine-4-(1-oxidothiomorpholine)-5-nitro-6-(2-pyridylaminoZ-pyrimidine) and methanolic hydrochloric acid. The product melts with signs of decomposition at a temperature of 237.5-240°C, and the yield is 73% of the theoretical yield. Example LX. 2-formylpiperazine-4-(1-o'oxy-dotiomo;r! foLno/-5-nitro-i6-/4-pyridylqamino/-pyrimidine. This compound is prepared. in a manner analogous to that described in Example XLIX, with 2-formylopi- perazine-4-(1-oxidithioniophoroline)-i5-nitro-6-chloropyrimidine and 4-aminopyridine. The product melts at 240-243°C, theoretical yield. Example LXI. 2-Piperazine-4-(1-oxidothio'morpholino/-15-nitro-6-/4-pyridylamino/-pyrimidine dihydrochloride. This compound is prepared in a manner analogous to that described in Example XXXIX, from 2-formyl-piperazine-4-/1-oxidothiomorpholino/-5-nitro-6-/4- -pyridylamino/-pyrimidine and methanolic hydrochloric acid. The product melts with symptoms of decomposition at a temperature of 335°C, and the yield is 81.8% of the theoretical yield. Example LXII. 2-piperazine-4-(1,1-dioxydothiomorpholino)-5-nitro-6-cyclohexylaminopyrimidine. To a solution of 68 g of 2-piperazine-4-(1-dioxydothiomorpholino)-5-nitro-6-cyclohexylaminopyrimidine cooled to 10°C in 100 ml of 2N sulfuric acid, a solution of 0.316 g of potassium permanganate in 20 ml of 2N sulfuric acid is added dropwise over 15 minutes, then the mixture is left for 3 hours at 10°C and then the separated brown crystals are filtered off. This product is mixed with 30 ml of water, excess concentrated ammonium hydroxide is added to the resulting suspension and extracted with chloroform. The extract is evaporated and the residue is recrystallized from ethanol to obtain 0.25 g (19% of theoretical yield) of 2-piperazine-4-(1,1-dioxydothiomorpholino)-5-nitro-6-cyclohexylaminopyrimidine, melting point 214-216°C. Example LXIII. 5-carboethoxy-2-piperazine-4-thiomorpholinopyrimidine. This compound is prepared in a manner analogous to that described in Example LXVI, from 2-chloro-5-carboethoxy-4-thiomorpholinopyrimidine with a melting point of 70-71°C with piperazine in dioxane /2 hours, 1'00°C/. The yield was 17.5% of theory, and the product melted at 115°C (from gasoline and benzene). Example 64. 2-Piperazino-4-(1-oxydothiomorpholino)-5-fluoropyrimidine. This compound was prepared in a manner analogous to that described in Example 66 by boiling 2-chloro-4-(1-oxidothiomorpholino)-5-fluoropyrimidine with piperazine in dioxane for 2 hours. The yield was 64% of theory, and the product, converted into the dichlorofluoride hemihydrate, melted at 203-205°C (from ethanol diluted with water). Example 65. 6-Ethoxy-5-nitro-2-(1-oxydothiomorpholino)-4H-piperazinopyrimidine. This compound is prepared by the action of hydrogen peroxide at 20°C for 1 hour on 6-ethoxy-5-nitro-4-piperazine-2-thiomorpholinopyrimidine, melting point 84-86°C. The product, recrystallized from isopropanol and petroleum ether, melts at 108-110°C. Example LXVI. 6-ethoxy-5-nitro-2-piperazine-4-thiomorpholinopyrimidine. To 68 g (0.8 mol) of molten piperazine, 23 g (0.07 mol) of 6-ethoxy-2-methylthio-5-nitro-4-thiomorpholinopyrimidine are added and heated for 1 hour at 100°C, then cooled and ice water added to the mixture. The yellow precipitate obtained was filtered off, washed with water and recrystallized from isopropanol, yielding 18 g (70% of theory) of 6-ethoxy-5-nitro-2-piperazine-4-thiomorpholinopyrimidine, melting at 166.5-168.5°C. Analysis of the product: Formula C14H22Np3S (354.3). Calculated: 47.44% C, 6.26% H, 0.05% S. Found: 47.50% C, 6.23% H, 9.02% S. Example LXVII. 6-Ethoxy-5-nitro-4-(1-oxidothiomorpholino)-2-piperazinopyrimidine. This compound was prepared in a manner analogous to that described in Example 66, by reacting 6-ethoxy-2-methylthio-5-nitro-(1-oxidothiomorpholino)-pyrimidine with piperazine for 20 minutes. The product, recrystallized from ethanol, melts at 23°C-224°C. Example 68 6-allyloxy-5-nitro-2-piperazine-4-thiomorpholinopyrimidine. This compound is prepared in a manner analogous to that described in Example LXVI, by reacting 6-alyloxy-2Hmethylthio-5-nitro-4-thiomorpholinopyrimidine with piperazine for 15 minutes at a temperature of 120°C. form of the free base from 0.5 mole of crystallization water melts at a temperature of 132-133°C (from carbon tetrachloride from gasoline). Example LXIX. 6-Allyloxy-4[1,1-dioxydothiomorpholino]-5-nitro-2[2-piperazine-pyrimidine]. This compound was prepared in a manner analogous to that described in Example 66, by reacting 4[beta]-allyloxy-[beta]-dioxydothiomorpholino]-methylthio-5-nitropyrimidine with piperazine at 120°C for 4 minutes. The product melts at 143-147°C (from isopropanol). Example 6XX. 6-n-propoxy-4-(1,1-di-45 oxidothiomorpholino)-5-nitro-2-piper.azinopyrimidine. This compound is prepared in a manner analogous to that described in Example LXVI, by the reaction 6-n-pro:poxy-4-vfl4-dio! xydothio|morpholino/-,2-methylthio-5-nitropyrimidine with piperazine at 120°C for 20 minutes. The product recrystallized from carbon tetrachloride melts at a temperature of 166-169°C. Example LXXI. 6-n-propoxy-5-nitro-4-(1-55-oxydothiomortfolino/12-piperazinepyrimidine. This compound is prepared in a manner analogous to that described in Example 66, by reacting [e]-[1,1-propoxy-[1-methylthio]-[1-oxidothiomorpholino]-5-nitro-2-piperazine with piperazine at 60-120°C for 20 minutes. The product, recrystallized from aqueous ethanol, melts at 170.5-72.5°C. Example 6XXII. 4-[1,1-dioxidothiomorpholino]-5-nitro-2-piperazine-6-isopropoxypyrimidine. This compound was prepared in a manner analogous to that described in Example 66, by reacting 4-(1,1-dioxydothiomorpholino)-(3-methylthio-S-nitro-6-isopropoxypyrimidine with piperazine at 120°C for 20 minutes. The product recrystallized from ethanol melts at 2°C. Example LXXIII. 6-Nuthoxy-5-nitro-4-(1-(oxidothiomorpholino)-2-piperazinopyrimidine). This compound is prepared in a manner analogous to that described in Example LXVI, by reacting 6-nH-butoxy-2-methylthio-5-nitro-4-(1-oxidothioanorpholine)-pyrimidine with piperazine at 130°C for 15 minutes. The product, converted into the hydrochloride and recrystallized from ether with acetone, melts, with symptoms of decomposition, at 160°C. Example LXXIV. 6-neopentyloxy-5-nitro- -2-Piperazine-4-thiomorpholinopyrimidine. This compound is prepared in a manner analogous to that described in Example 66 by reacting 2-methylthio-6-neopentyloxy-5-nitro-4-thiomorpholinopyrimidine with piperazine at 130°C for 30 minutes. The product, recrystallized from ethyl acetate, melts at 130°H2SO4. Example 6XV. 5-Nitro-2-piperazine-6-isopropoxy-4-thiomorpholinopyrimidine. This compound is prepared in a manner analogous to that described in Example 66 by reacting 2-methylthio-5-nitro-6-isopropoxy-4-thiomorpholinopyrimidine with piperazine at 130°C for 30 minutes. in 15 minutes. The product recrystallized from isopropanol melts at 137.5-140°C. Example 6XVI. 5-Nitro-4-(1-oxidothiomorpholino)-2-piperazine-6-isopropoxypyrimidine. This compound is prepared in an analogous manner to that described in Example 6XVI, by reacting 6-isopropoxypyrimidine with piperazine at 130°C for 15 minutes. The product recrystallized from isopropanol melts at 204.5-206°C. Example 6XVII. 6-n-Butoxy-4-(1,1-dioxidothiomorpholino)-5-nitro-2-piperazinepyrimidine. This compound is prepared in an analogous manner to that described in Example 6XVI. Example 66: 6-n-Butoxy-4-(1-dioxydothiomorpholino)-2-methylthio-5-nitropyrimidine with piperazine at 130°C for 15 minutes. The product, recrystallized from aqueous ethanol, melts at 181°C-183°C. Example 66: 6-n-Butoxy-5-nitro-2-piperazine-4-thiomorpholinopyrimidine. This compound is prepared in a manner analogous to that described in Example 66: 6-n-Butoxy-2-methylthio-5-nitro-4-thiomorpholinopyrimidine with piperazine at 130°C for 10 minutes. The product, recrystallized from aqueous ethanol, melts at 181°C-183°C. from isopropanol, melting point 1.17-111°C. Example LXXIX. 6-n-Butoxy-4-morpholino-5-nitro-2-piperazinopyrimidine. This compound was prepared in a manner analogous to that described in Example LXVI, by reacting 6-n-butoxy-2-methylthio-4-morpholino-5-nitro-piperazinopyrimidine with piperazine for 16 minutes at 120°C. The product, recrystallized from aqueous methanol, melting point 63-65°C. Example LXXX. 4-Morifolino-5-nitro-2-piperazino-6-isopropoxypyrimidine. This compound was prepared in a manner analogous to that described in Example LXVI, by reacting 2-Methylthio-4-immorpholino-5-nitro-6-isopropoxypyrimidine with piperazine in 10 minutes at 130° C. The product recrystallized from isopropanol melts at 117-119° C. Example 831. 6-Secondary butoxy-5-nitro-2-piperazine-4-thiomorpholinopyrimidine. This compound is prepared in a manner analogous to that described in Example 86, by reacting 6-sec. butoxy-2-methylthio-5-nitro-4-thiomorpholinopyrimidine with piperazine at 130° C for 20 minutes. The product recrystallized from petrol melts at 123-126° C. Example LXXXII. 6-Secondary butoxy-5-nitro-4-(1-oxidothiomorpholino)-2-piperazinopyrimidine. This compound was prepared in a manner analogous to that described in Example LXVI, by reacting 6-sec. butoxy-2-methylthio-5-nitro-4-(1-oxidothiomorpholino)-pyrimidine with piperazine at 130°C for 20 minutes. The product, recrystallized from petrol with carbon tetrachloride, melts at 156-158°C. / Example LXXXIII. 6-Secondary butoxy-4-(1,1-dioxidothiomorpholino)-5-nitro-2-piperazinopyrimidine. This compound was prepared in a manner analogous to that described in Example LXVI, by reacting 6-sec.-butoxy-4-(1,1-dioxydothiomorpholino)-2-methylthio-5-nitropyrimidine with piperazine at 130°C for 20 minutes. The product, recrystallized from carbon tetrachloride, melts at 13°C-104.5°C. EXAMPLE LXXXIV. 6-Ethoxy-4-(1,1-dioxydothiomorpholino)-5-nitro-2-piperazinopyrinlidine. This compound is prepared in a manner analogous to that described in Example LXXI, by reacting 6-ethoxy-4-(1,1-dioxydothiomorpholino)-2-methylthio-5-nitropyrimidine with piperazine at 120°C for 20 minutes. 20 minutes. The product crystallizes from 0.5 mole of water of crystallization, melts at 190-193°C (from carbon tetrachloride). Example LXXXV. 4-Morpholino-5-nitro-2-piperazine-6-n-propoxypyrimidine. This compound is prepared in a manner analogous to that described in Example LXVI, by reacting 2-methylthio-4-morpholino-5-nitro-6-n-propoxypyrimidine with piperazine at 120°C for minutes. The product recrystallized from petrol, melts at 10.1-104°C. Example LXXXVI. 5-Nitro-2-piperazine-6-n-propoxypyrimidine. -n-propoxy-4-thiomorpholinopyrimidine. This compound is prepared in a manner analogous to that described in Example LXVI, by reacting 2-methylthio-5-nitro-6-n-propoxy-4-thiomorpholinopyrimidine with piperazine at 120°C for 60 minutes for 20 minutes. The product recrystallized from gasoline melts at a temperature of 92-95°C. EXAMPLE LXXXVII. 6-ethoxy-5-cyano-4-(1,1-dioxydo'thiomorpholino)-2-piperazinopyrimidine. 65 This compound is prepared in a manner analogous to that described in Example LXVI, by the reaction 6-ethoxy-5-cyano-2-methylthio^-/1,1-dioxidothio- morpholino-2-pyrimidine, melting point 194°C, with piperazine at 130°C within 30 minutes. The product, recrystallized from ethanol, melts at 235°C. Example LXXXVIII. 6-Ethoxy-5-cyano-4-morpholino-2-piperazinopyrimidine. This compound is prepared in a manner analogous to that described in Example LXVI, by reacting 6-ethoxy-5-cyano-2'-methyl-2'-thio-4-morpholinopyrimidine, melting point 104°C, with piperazine at 120°C within 30 minutes. The hydrochloride of this compound melts at 239°C (from ethanol). Example LXXXIX. 6-Ethoxy-5-cyano-2-piperazinopyrimidine. perazine-4-thiomorifblinopyrimidine. This compound is prepared in a manner analogous to that described in Example LXVI, by reacting 6-ethoxy-'5-cyano-2-methylthio-4-thio,morpholinopyrimidine with a melting point of 157-159°C with piperazine. These reactions are carried out at 130°C for 30 minutes. The product recrystallized from ibenzine melts at 119°C. Example XC. 5-cyano-6-methoxy-4-(l-oxy-dothiomorpholino)-2-piperazinopyrimidine. This compound is obtained in a manner analogous to that described in Example LXVI, by the reaction 5-cyano-6-methoxy-2-methylthio-4-(l-oxido- Thiomorpholino-Z-pyrimidine, melting point 184-186°C, with piperazine. The reaction is carried out for 30 minutes at 130°C. The product recrystallized from water melts with signs of decomposition at 270°C. Example 91. 5-Cyano-4-(1-oxidothiomorphina)-2-pyretazino-6-n-propoxypyrimidine. This compound is prepared in a manner analogous to that described in Example 66, by reacting -cyano-2-methylthio-4-(1-oxidothiomorphina)-6-n-propoxypyrimidine, melting point 190-192°C, with piperazine. The reaction is carried out at 130°C for 1.5 hours. The product recrystallized from water melts at temperature 177-179°C. * Example XCII. 5-cyano-4-morpholino-2-piperazine-6-n-propoxypyrimidine. This compound is prepared in a manner analogous to that described in Example LXVI, by the reaction of 5-cyano-2-methylthio-4Hmorpholino-6-n-propoxypyrimidine, melting point 107°C, with piperazine. The reaction is carried out at 130°C for 1.5 hours. The hydrochloride of this compound decomposes at temperatures above 230°C. Example XCIII. 5-cyano^2-piperazine-6-n-propoxy-4-thiomorpholinopyrimidine. This compound is prepared in a manner analogous to that described in Example LXVI, by the reaction -cyano-2-methylthioj6-n-propoxy-4-thiomorpholino-pyrimidines, melting point 120-122°C, with piperazine at 130°C in 1 hour. The hydrochloride of this compound recrystallized from ethanol melts at 248°C. Example XCIV. 6-ethoxy-5-cyano-4-(1-oxydothiomorpholino/u2-piperazinopyrimidinal 44) This compound is prepared in a manner analogous to that described in Example LXVI, by the reaction of 6-ethoxy-5-cyano-2-methylothio-4-(1-oxidothiomorpholino)pyrimidine with a melting point 190°C with piperazine. The reactions are carried out at 120°C for 1 hour. The product crystallizes from 0.5 mole of water and, when recrystallized from water, melts at 205°C. Example 16V. 6-Ethoxy-5-formyl-2-piperazine-4-thiomorpholinopyrimidine. This compound is prepared in a manner analogous to that described in Example 6V, by reacting 6-ethoxy-5-formyl-2-methylthio-4-thiomorpholinopyrimidine, melting point 101°C, with piperazine. The reaction at 130°C lasts 1 hour. The product, when recrystallized from petrol, melts at 110-113°C. Example 16V. 6-Ethoxy-5-formyl-4-(1-)- -(1-oxydothiomorpholino)-2-piperazinopyrimidine. This compound was prepared in a manner analogous to that described in Example 66, by reacting 6-ethoxy-5-formyl-2-methylt6-4-(1-oxidothiomorpholino)-pyrimidine, melting point 163°C, with piperazine. The reactions were carried out at 140°C for 1 hour. The product, recrystallized from ethyl acetate, melts at 180°C. Example XCVII. 6-Ethoxy-5-nitro-4-(1-oxidothiomorpholino)-(2-piperazinopyrimidine). 52 g (0.6 mole) of piperazine were dissolved in 120 ml of boiling dioxane and 61.5 g (0.18 mole) of 6-ethoxy-2-methylthio-5-nitro-4-(1-oxidothiomorpholino)pyrimidine were added to the solution over 30 minutes. The mixture was then boiled under reflux for 45 minutes and then poured into 1.5 liters of ice-cold water, the yellow precipitate was filtered off, washed with water and recrystallized from ethanol. 46.1 g (65.8%) of 6-ethoxy-5-nitro-4-(1-oxidothiomorpholino)pyrimidine (theoretical yield) were obtained. zinopyrimidines, melting point 222-23°C. Example XCVIII. 5-cyanoJ6-methoxy-2-piperazine-4-thiomorpholinopyrimidine* 45 This compound is prepared in a manner analogous to that described in Example dioxane, at 100°C in body temperature - 50 Su 8 hours. The hydrochloride of this compound, recrystallized from ethanol, melts with symptoms of decomposition at a temperature of ^°C. Example XCIX. 6-Ethoxy-5-nitro-4-(1-oxidothiomorpholino)-2-piperazine-pyrimidine. 50 g (0.15 mole) of 6-ethoxy-2-methylthiomorpholino)-2-pyrimidine and 64.6 g (0.15 mole) of piperazine were dissolved in 150 ml of diethyl sulfoxide and stirred at room temperature for 6 hours. The mixture was poured into ice-cold water, the crystalline product was filtered off, washed with water, and recrystallized from ethanol. 39.3 g (70.7%) of theoretical yield of 6-ethoxy-2-nitro-(1-oxidothiomorpholino)-2-piperazine-pyrimidine was obtained, melting point 222-223°C. 65 By treating an ethanolic solution of the obtained base with an equivalent amount of the appropriate acid, for example, the following salts of this base are obtained: the maleate, C18H2ffH, melting at 180-185°C (from ethanol); the fumarate, AsHseSNtfOaS, hygroscopic, melting at 222-1224°C; the p-toluenesulphonate, C21H3oN6O7S2, melting at 133-137°C (from a small amount of methanol); and the succinate, C16H2sNdO6S, melting with symptoms of decomposition at 194-196°C (from methanol). Example C: 6-Methoxy-5-nitro-4-(1-oxidothiomorpholino)-2-piperazinopyrimidine. This compound was prepared in a manner analogous to that described in Example XCVIII, by reacting 6-methoxy-2-methylthio-5-nitro-4-(1-oxidothiomorpholino)-pyrimidine with piperazine in dimethyl sulfoxide for 4 hours at 20°C. The product, recrystallized from isopropanol, melts at 17.5°C. Example C: 6-Ethoxy-5-nitro-4-(1-oxidothiomorpholino)-2-piperazinopyrimidine. 12 g 70.037 mol/ <6-ethoxy-2-chloro-5-nitro-4-(1-oxydothiomorpholino)-pyrimidine and 22 g (0.28 mod) of piperazine are stirred in ethanol at 40°C for 2 hours, then the mixture is poured into water, the precipitate is filtered off and recrystallized from ethanol. 13 g (93.8% of theoretical yield) of 6-ethoxy-2-chloro-5-nitro-4-1-approx. are obtained. sidothiomorpholino/-pyrimidines with a melting point of 223-224°C. Product analysis: Formula C^H^gO^ 7370.4/. Calculated: 45.39% C, 5.99% H, 8.66% S. Found: 45.30% C, 5.97% H, 8.56% S. Example CII. 2,6-Di-(1-oxidothiomorpholino-M-morphomno-S-nitropyrimidine. This compound was prepared in a manner analogous to that described in Example C, by reacting 2,6-dichloro-4-morpholino-5-nitropyrimidine, m.p. 129-130°C, with 1-oxidothiamorpholine in ethanol at 20°C for 1 hour. The product melts at 250°C. Example CIII. 6-Ethoxy-5-nitro-4-piperazine-2-thiomorpholinopyrimidine. This compound was prepared in a manner analogous to that described in Example C, by reacting 6-ethoxy-4-chloro-5-nitro-2-thiomorpholinopyrimidine with piperazine in ethanol at 78°C for 1 hour. The product melts at 84-86°C (from isopropanol with ethyl acetate). Example CIV. 5-cyano-6-methoxy-4-piperazine-2-thiomorpholinopyrimidine. 18 g (0.067 mol) of 4-chloro-6-cyano-6-methoxy-2-thiomorpholinopyrimidine, melting point 218-219°C, were mixed with 0.3 g of 70.7 mmol of piperazine and heated at 130°C for 3 hours. The mixture was then cooled, treated with water and extracted with chloroform. The extract was dried, evaporated with chloroform under reduced pressure, the residue was dissolved in hot ethanol and 5-cyano-6-methoxy-4-piperazine-2-thiomorpholinopyrimidine hydrochloride was precipitated from the solution with ethanolic hydrochloric acid. The precipitate was filtered off and washed with ethanol, yielding 13 g (754.8% of theory), melting point 261°C. Analysis of the product: Formula C^Hg1CINoOS (356.81). Calculated: 47.18% C, 5.93% H, 23.52% N, 8.98% S. Found: 46.90% C, 5.90% H, 23.55% N, 8.96% S. Example CV. 16-ethoxy-5-nitro-2-piperazine-4-(1-oxidothiomorpholino)-pyrimidine. This compound is prepared by preparing 2 g of 76 mmol/2,6-diethoxy-5-nitro-4-/1-oxidothiomorpholino/pyrimidine with a melting point of 130-13t2°C and 8.6 g 7100 millimoles of piperazine are heated at 125°C for 4 hours, then the mixture is poured onto ice, the separated crystalline product is filtered off and recrystallized from ethanol. 0.53 g of 723.6% of the theoretical yield are obtained, melting at a temperature of 221-212°C. Example CVI. 6-Ethoxy-5-nitro-4-(1-oxido-thiomorpholino)-2-piperazinopyrimidine. 3.6 g (0.01 mole) of 6-ethoxy-5-nitro-2-piperazine-4-thiomorpholinopyrimidine was dissolved in 100 ml of methanol, treated with a solution of 2.2 g (70.01 mole) of sodium metaperiodate in 50 ml of water and boiled under reflux for 4 hours. The mixture was then poured into water and extracted with chloroform. The extract was dried, the chloroform was distilled off under reduced pressure, and the residue was recrystallized from ethanol. 2.9 g of 777% of theoretical yield of 6-ethoxy-5-nitro-4-(1-oxidothiomorpholine)-2-piperazinopyrimidine with a melting point of 223-224°C are obtained. Example CVII. 6-ethoxy-5-nitro-4-(1-oxy-dothioformyl)-2-piperazinopyrimidine. 1 g (2.9 mmol) of 6-ethoxy-2-methylsulfinyl-5-nitro-4-(1-oxidothiomorpholino)pyrimidine, melting at 164-165°C, obtained by reacting 6-ethoxy-2-methylthio-5-nitro-4-(1-oxidothiomorpholino)pyrimidine with hydrogen peroxide in dilute acetic acid, was mixed with 5 g (58 mmol) of piperazine in 50 ml of ethanol and boiled under reflux for 1 minute. The mixture was then poured into water and extracted with chloroform. The extract is dried, evaporated to dryness and the residue is crystallized from ethanol, obtaining 0.9 g of 784.7% of theoretical yield/6-ethoxy-5-nitro-4-/1HDoxydothiomorpholino/-2-piperazinopyrimidine, melting point 220- -222°C.Example CVIII. 6-ethoxy-5-nitro-4-(1-oxy-dothiomorpholino)-2-piperazinopyrimidine. This compound is prepared by taking 1.2 g (3 mmol) of 6-ethoxy-2-(N-formylpiperazine)-5-nitro-4-(1-oxydothiomorpholino)pyrimidine with a melting point 209-211°C and 1.2 g of 730 mmol/55 sodium hydroxide in 80 ml of methanol are refluxed for 3 hours, then the mixture is poured into water and extracted with chloroform. The extract was dried and the chloroform was evaporated under reduced pressure, yielding 1 g (89.6% of theory) of the product, which, after recrystallization from ethanol, melted at 222-223°C. Example CIX. 5-cyano-6-methoxy-fl-Zl-oxydothiomorpholinoM-piperazine-65 pyrimidine hydrochloride.37 93115 38 2.04 g /0.01 mol/ 5-cyano-2,4-dichloro-6-methoxypyrimidine with a melting point of 112°C is dissolved in 50 ml dlyoxane, add 2 g of potassium carbonate in 10 ml of water and cool it to 0°C, then, while stirring and cooling, a solution of 1.19 g (0.01 mol) of 1-oxidothiomorpholine in 20 ml of dioxane is added dropwise. The 5-cyano-4-chloro-6-methoxy-2-(1-)-oxidothiomorpholino-pyrimidine contained in the mixture was further reacted with 4.3 g (0.05 mol) of piperazine, stirring at room temperature for 3 hours. Water was then added and the mixture was extracted with chloroform. The extract was dried over sodium sulfate, evaporated, and the residue purified by column chromatography on Merck silica gel, 0.2-0.5 mm, eluting with methanol/ammonia 10:1. Homogenous fractions were combined, evaporated to dryness, the residue was dissolved in ethanol, and 5-cyano-6-methoxy-2-(1-)-oxidothiomorpholino-pyrimidine hydrochloride was precipitated by adding ethanolic hydrochloric acid. lino/-4jpiperazinopyrimidines. I obtain 2.2 g (59% of theoretical yield) of a product that melts with symptoms of decomposition at a temperature above 243°C. Product analysis: Formula C14H21GLN602S. /372.89/. Calculated: 45.09% C, 5.67% H, 22.53% N. Found: 44.85% C, 5.57% H, 22.45% N. Example CX. 5-cyano-2-(1,1-dioxydothiomorpholino)-6-methoxy-4-pilperazinopyrim;idine. This compound is prepared in a manner analogous to that described in Example CXVII, by reacting -cyano-2,4-dichloro-6-methoxypyrimidine with a melting point of 112°C with 1,1-dioxydothiomorpholine and piperazine. The hydrochloride of this compound melts with symptoms of decomposition at a temperature of 237°C. Example CXI. 6-neopentyloxy-5-nitro-4-(l-oxydbthiomorpholino)-2-pliperazinopyrimidine. 4.5 g (0.011 mol) of O-neopentyloxy-5-nitro-2-piperazine-4-thiomorpholinopyrimidine were mixed with 60 ml of water and 11.4 ml (0.022 mol) of 2N hydrochloric acid. To the resulting suspension was added 1.66 g (0.011 mol) of hydrogen peroxide and stirred at room temperature for 24 hours. The resulting solution was made alkaline by carefully adding 12 ml of 2N sodium hydroxide solution. The precipitate was filtered off, washed with water and crystallized from a mixture of 30 ml of methanol and 20 ml of water. I obtain 2.4 g (51.2% of theoretical yield) of 6-neopentyloxy-5-nitro-4-(1-oxidothiomorpholino)-2-piperazinopyrimidine with a melting point of 156-1-58°C. Product analysis: Formula C17H2^NfiS (412.51). Calculated: 49.50% C, 0.87% H, '20.37% N, 7.77% S. Found: 49.30% C, 0.76% H, 20.43% N, 7.7 and 6% S. Example CXII. 2,6-diethoxy-5-n! itro-4-(l-oxidothiomorpholino)-pyrimidine. 3.0 g (793 mmol) of 6-chloro(2-methylthio-5-nitro-4-(1-oxidothiomorpholino)pyrimidine, m.p. 1218-131°C, are added at room temperature to a solution of sodium ethoxide prepared from 0.22 g (0.0094 gram-atom) of sodium and 30 ml of ethanol, and the mixture is heated under reflux for 2 hours and then left at room temperature for 20 hours. The mixture is poured into water, extracted several times with chloroform and ethanol, the combined extracts are dried and evaporated to dryness. The residue is recrystallized from a mixture of ethyl acetate and gasoline, obtaining 2 g (65% of theoretical yield) of 2,6-diethoxy-5-,nitro-4-,(1-oxidoliomorpholino)-pyrimidine with a melting point of 130-132°C. Product analysis: Formula C12H18Np5S /330.35/. Calculated: 43.63% C, 6.49% H, 16.96% N. Found: 43.70% C, 5.38% H, 16.80% N. Example CXIII. 2-(N-Carboethoxypiperazino)-6-methoxy-5-nitro-4-thiomorpholinopyrimidine. This compound is prepared in a manner analogous to that described in Example 1, by reacting 2-(N-Carboethoxypiperazino)-6-chloro-5-nitro-4-thiomorpholinopyrimidine, melting at 134.5°-136.5°C, with sodium methoxide in methanol in the presence of small amounts of dimethyl sulfoxide and potassium iodide. The reaction is carried out at 50°C for 12 hours. The product, recrystallized from methanol, melts at 158-159°C. Example CXIV. 6-Ethoxy-5-nitro-4-(1-oxidothiomorpholino)-2-pyrimidine. To 3 ml of concentrated sulfuric acid is added 1 g of 6-ethoxy-2-pyrazino-4-thiomorpholinopyrimidine, whereupon the temperature of the resulting suspension is raised to 50°C. After cooling to 0°C, 2 ml of concentrated nitric acid is added dropwise with stirring, the mixture is stirred for 1 hour at room temperature, the mixture is filtered through glass wool and the filtrate is stirred with ice water. Then 40% sodium hydroxide solution is carefully added until pH = 9 and the mixture is extracted with chloroform. The mixture was washed with water, dried over sodium sulfate and the solvent was evaporated under reduced pressure. The residue was recrystallized from ethanol, yielding 0.8 g (66.9% of theory) of O-ethoxy-5-nitro-4-(1-oxidothiomorpholino)-2-piperazinopyrimidine, melting at 223°-24°C. Example 25: 2-(N-Carloxypropionylpiperazinide)-6-methyl-5-nitro-4-(1-oxidothiomorpholino)-pyrimidine. 3.4 g (0.01 mole) of 6-methyl-5-nitro-4-(1-oxidothiomorpholino)-2-piperazinopyrimidine, melting at 50°C. 170-178°C, obtained by the reaction of 2-(chloro-6-methyl-5-nitro-4-(1-oxidothiomorpholine)-pyrimidine with piperazine in a mixture of acetone and dioxane, with cooling, was dissolved in 200 ml of acetone and, with stirring, added slowly a solution of 1.2 g (0.012 mole) of succinic anhydride in 30 ml of acetone. After several hours, the crystalline reaction product was filtered off, washed with a small amount of ethanol and water (1:1) and dried, yielding 3.7 g of 2-(N-carboxypropionyl)-6-piperazine (theoretical yield). -methyl-5-nitro-4-(1-oxidothiomorpholino)-pyrimidine. After recrystallization from ephenol/water 71:1/, the product melts at 221-223°C. 65 Example CXVI. 2-(N-acetoacetylpiperase-IX9 no/^-methyl^nitro-4r/l-oxy*dotiqimrfoaiino/-pyrimidine. To a suspension of 3.4 g (0.01 mol) of 6-methyl-5-nitro-^-/l-ofey4othiomor^too/-2-piperazinopyrimidine in approximately 40 ml of dioxane is added slowly, stirring and cooling, a solution of 0.9 g (0.01 mol) of diphcetone in 10 ml of dioxane, then stirred for 1 hour at room temperature. The clear solution obtained was evaporated under reduced pressure and the oily residue was digested with a small amount of ethyl acetate, which crystallized after a short standing time. The precipitate was filtered off, washed with a small amount of methanol and dried, yielding 3.9 g (92% of theory) of 2-(N-acetoacetylpiperazino)-6-methyl-5-nitro-4-(1-oxidothiomorpholino)-pyrimidine. After recrystallization once from methanol, the product melted at 174-176°C. Example 77: 6-Methyl-2-(1N-nicotinoylpiperazino)-5-nitro-4-(1-oxidothiomorpholino)-pyrimidine To a solution of 3.5 g (0.02 mole) of nicotinic acid chloride hydrochloride in 60 ml of anhydrous pyridine was slowly added dropwise, with stirring at room temperature, a solution of 3.4 g (70.01 mole) of 6-methyl-5-nitro-4-(1-oxidothiomorpholino)-2-piperazinopyrimidine in 0.00 ml of pyridine, and stirred for 1 hour. The resulting solution was then concentrated under reduced pressure to a small volume, the residue was dissolved in a small amount of water, and after standing for a short time, the crystallized methyl-2-(N-lycotinoylpiperazino)-5-nitro-4-(1-) -okaydottomorpholino/-pyrimidine and immediately recrystallized it from ethanol, obtaining 3.4 g (76° theoretical yield) of product with a melting point of 145-148° C. Example CXVIII. 2-(N-isodicotinoylpiperazine/r6-methyl-5-nitro-4-/l-oxidothiomorphollino/-pyrimidine. This compound is prepared in a manner analogous to that described in Example CXVT, by reacting (N-methylH5-nitro-4-/lfoxydothiomorpholino/-2^piperazinopyrimidine chloride hydrochloride isonicotinoyl. The product melts at 208°C. Example CXJX. Dothiomorpholino]-2-(N-salicylpiperazine)-pyrimidine. This compound was prepared in a manner analogous to that described in Example CXVI from 6-methyl-5-nitro[4-(1-oxidothiomorpholino)-2-piperazinopyrimidine and salcycloyl chloride. The product melts at 143-146°C. Example CXX. 2-[N-(2-furoyl)-piperazino]-H6Tmethyl[4-nitro-4-(11-oxidothiomorpholino)-pyrimidine. This compound was prepared in a manner analogous to that described in Example CXVI from 6-methyl-5-nitro-4-(N-salicylpiperazine)-2-piperazinepyrimidine and salcycloyl chloride. furan-2-4Laitoonyl dissolved in dioxane. The product melts at a temperature of J»Q^m°C. Example CXXI. 2-(N1-methoxyacetylpiperazine)-6-methyl-5-nitro-4-(1-oxidothiomorpholino)-pyrimidine. 1115 40 This compound is prepared in a manner analogous to that described in Example CXVI, from 6-methyl-5-n;itro-4-(1-oxidothiomorpholino)2-12perazinopdrimidine and imethoxyacetyl chloride dissolved in dioxane. The product melts at 199-202°C. Example CXXII. 2-(N-carbamylpiperazino)-4-/1-oxy Dothiomorpholino[-5-nitro-6-methylmercaptopyrimidine]. 1.9 g of 2H-piperazino-4-(1-oxidothiomorpholino)-5-nitro-6-methylmercaptopyrimidine, m.p. 230°C, was dissolved in a mixture of 5 ml of glacial acetic acid and 10 ml of water, and a solution of 2.0 g of potassium cyanate in 25 ml of water was added dropwise at room temperature. Approximately 10 minutes after the addition was complete, crystallization of the product began. The crude product was recrystallized from ethanol, yielding 1.3 g (62.7% of theory) of 2-(N-canbamylpiperazino)-4-(1-oxidothiomorpholino)-5-nitro-6-methylmercaptopyrimidine. mercaptopyrimidine, which melts with signs of decomposition at 204°C. Example CXXIII. 2-(N-Methylcarbamylpiperazino)-4-(1-oxidothiomorpholino)-5-nitro-6-methylmercaptopyrimidine. 1.8 µg of 2-piperazino-4-(1-oxidothiomorpholino)-5-nitro-6-methylmercaptopyrimidine, m.p. 230°C, is stirred in 20 ml of dioxane, and to the resulting suspension is added dropwise over 5 minutes a solution of 1 ml of methyl isocyanate. After 10 minutes, three times the volume of water is added, and the mixture is shaken with a mixture of equal parts chloroform and ethanol. The extract is evaporated, and the residue is concentrated. crystallizes with acetone, obtaining 33 2.02 g ^97.3* (theoretical yield) of 2-(N-methyl-carpheamylpiperazineM-(1-oxidothiomorpholino)-5-nitro-6-methylmercaptopyrimidine, melting with symptoms of decomposition at 265°C. Example CXXIV. 2-YN-dimethylcarbamylpiperazino(-4-(1-o'oxydotdomorphoKno)-5-nitro-6-methylmercaptopyrimidine. 1.8 g of 2Hpiperazine-4-(1-oxidothiomorpholino)-5-n(i-tro-6-methylmercaptopyrimidine with a melting point of 230°C is mixed with dioxane containing 1.0 g triethylamine and to the resulting suspension slowly add 1.0 g of dimethylaminocarbamyl chloride, heat to 50°C and heat for 30 minutes, during which the mixture turns green. Then three times its volume of water was poured in, the mixture was extracted with chloroform, the extract was evaporated and the residue was recrystallized from acetone, yielding 2.1 g (98%) of theory) of 2-(N-dimethylcarbamylpiperazine)-4-(1-oxidothiomorpholine)HS-nitro-methylmercaptopyrimidine, melting at 213-280°C. Example CXXV 2-(N-in-butylcarba-mylopiperazine)-4-(1-olxidothiomoitfollino)-5-nitro-6-methylmercaptopyrimdine. This compound is prepared in a manner analogous to that described in Example CXXII, by reacting 1.0 g 2-piperazine-4-(1-oxydothiomoitphoHmo) 5-nitro-6-methylmercaptopyrimidine with a melting point of 230°C from 1.0 g of tert-butyl isocyanate. 1.20 g (94.8°C) of the theoretical yield are obtained, melting at 2»1°C,41 ttllS 42 Calculated: 45.95% C, 5.57% H, 17.86% N, 6.81% S. Found: 46.20% C, 5.78% H, 17.85% N, 6.79% S. Example CXXXI. 2-(N-nicotinylpiperazino)-4-(1-0'xidothiomorpholinoi)-5-nitrc-6-methylmer-captopyrimidine. 2.6 g of 2-piperazine-4-(1-oxydotnomorpholino)-5-natro-6-methylmercaptopiThymidine with a melting point of 230°C is mixed with 25 ml of anhydrous pyridine and 1.87 g of nicotinic acid chloride hydrochloride is added to the obtained suspension in portions, stirring, and then stirred for 1 hour, pyridine is distilled off, the residue is left with 100 ml of water for 3 hours, filtered off the precipitate and recrystallized from isopropanol. 1.25 g (33.2% of theory) of 2-(N-nicotinoylpiperazino)-4-(1-oxidothiomorpholino)-5-nitro-6-methylmercaptopyrimidine is obtained, which after recrystallization from isopropanol melts at 148-150°C. Example CXXXII. 2-(N-nicotinoylpiperazino)-4-(1-oxidothiomorpholino)-5-nitro-6-methylmercaptopyrimidine. This compound is prepared in a manner analogous to that described in Example CXXX, by reacting 2.6 g 2-piperazine-4-(1-oxidothiomorpholino)-5-nitro-6nmethylmercaptopyrimdine, melting point 230°C, with 2.50 g of isondocotin chloride hydrochloride. The yield is 17.5% of the theoretical yield, and the product recrystallized from isopropanol melts at a temperature of 140-142°C. Example CXXXIII. 2-(N-carboxyacryloyl-piperazineZ-?-methyl-5-nitro-4-(1-oxidothiomorpholino)-pyrimidine. This compound is prepared in a manner analogous to that described in Example CXIV, by reacting 2-piperazinoJ6-methyl-5-nitro-4-(1-oxidothiomorpholino)-pyrimidine with anhydride The product sintered at temperatures above 95°C. Analysis of the product: Formula CnH^O^S (438.5%). Calculated: 46.56% C, 5.05% H, 7.31% S. Found: 46.50% C, 6.32% H, 7.26% S. Example CXXVI. 2-(N-Methoxymethylcarbamylpiperazine-(1-oxidothiomorpholino)-5-nitro-6-methylmercaptopyrimidine* This compound was prepared in a manner analogous to that described in Example CXXIII, by reacting 1.8 g of 2-piperazine-(4-(1-oxidothiomorpholino)-5-nitro-6-methylmercaptopyrimidine, m.p. 230°C, with 0.8 g of methoxymethyl isocyanate. 1.9 g (86% of theory) of a product melting with decomposition symptoms at 202-210°C are obtained. Example CXXVII. 2-(N-methylsulfonylpiperazino)-4-(1-oxidothiomorpholino)-5-nitro-6-methylmercaptopyrimidine. This compound is prepared in a manner analogous to that described in Example CXXIII, by reacting 1.8 g of 2-piperazino-4-(1-oxidothiomorpholino)-5-nitro-6-methylmercaptopyrimidine, melting at 230°C, with 1.0 g of methyl sulfoxide in the presence of 1 g of triethylamine. 0.9 g (40% of theory) of product, melting point 238-237°C. Example CXXVIII. 2-(N-Carboethoxypiperazino)-4-(1-oxidothiomorpholino)-5-(nitro-6-methylmercaptopyrimidine). 4.0 g of 2-(N-Carboethoxypiperazino)-4-(1-oxidothiomorpholino)-5-nitro-6-chloropyrimidine, melting point 176-178°C, was dissolved in 10 ml of methanol and slowly added dropwise to a solution of 0.7 g of potassium ethanol in 40 ml of methanol treated with 1.5 ml of liquid methyl mercaptan. Stirred for 2 hours, diluted with 100 ml of water. and extracted with chloroform. The extract is dried over sodium sulfate, evaporated and the residue recrystallized from acetone to obtain 3.3 g (G9.1% of theoretical yield) of 2-(N-carboethoxypiperazine)-4-(1-oxidothiomorpholino)-5-nitro-6-methylmercaptopyrimidine with a melting point 1911-196°C.Example CXXIX. 2-(N-acetoacetylpiperazine)-6-ethoxy-5^nitro-4-(l-o'oxydothiomorpholano)-pyrimidine. This compound is prepared in a manner analogous to that described in Example CXXV, by the reaction of 6-ethoxy-5-ndtro-2-piperazine-4-(yl-oxydothiomosipho- lino/-pyrimidines with a melting point of 223-224°C with a diketone. The yield is 55% of the theoretical yield, and the product recrystallized from ethanol melts at 191-192° C. Example CXXX. N-[6-ethoxy-5-nitro-4-(1-oxydothiomortphohvno)-ptirymidin-2-yl]-N-(3-carboxypropionyl)-piperazine. 3.75 g (0.01 mol) of 6-ethoxy-5-nitro-4-(1-oxidothiomorphodino)-2-piperazinopyrimidine with a melting point of 223-224°C and 2.0 g (0.02 mol) of freshly distilled succinic acid anhydride are mixed with 50 ml of dioxane and refluxed for 1 hour, then evaporated to dryness and the solid residue recrystallized twice from a mixture of ethyl and apropane. 2.0 g (42.5% of theoretical yield) of N-methyl-ethoxy-5-nitro-4-(1-oxydothiomoirfoMno.-pi,rimidin-2-yl]-N,-(3-karr boxypropiayl)-pipefazine with a melting point of 1-8-200°C are obtained. Analysis of the product: Pattern d^B^ffi-jS /470,51/.PL PL PL PL PL PL PL PL PL PL

Claims (1)

1.